https://proteopedia.org/api.php?action=feedcontributions&feedformat=atom&user=Kurt+GilesProteopedia - User contributions [en]2026-09-16T06:45:09ZUser contributionsMediaWiki 1.43.8https://proteopedia.org/index.php?title=Group:SMART:Teams&diff=952104Group:SMART:Teams2009-04-29T23:31:05Z<p>Kurt Giles: </p>
<hr />
<div>=Overview of the Program=<br />
[[Image:SMART Teams photo 1.jpg|left]]<br />
[[Image:Smart Teams photo 5.jpg|right|200px]]<br />
<br />
What do you get when you combine enthusiastic high school teachers and their students, scientists excited about their research, and Rapid Prototyping technology? <font color = 'red'>SMART</font> (<font color = 'red'>S</font>tudents <font color = 'red'>M</font>odeling <font color = 'red'>A R</font>esearch <font color = 'red'>T</font>opic) Teams! In this multi-faceted program, students develop teamwork as they delve into the molecular world, explore science as a process and not just a collection of facts, and work closely with a researcher to understand and model the structure-function relationship of a protein the researcher studies. After designing and building a model of the protein using Rapid Prototyping technology, SMART teams create an oral presentation explaining their work to a lay audience and a poster which is presented to a scientific audience.<br />
<br />
SMART Teams consist of a teacher who has participated in the Center for BioMolecular Modeling's summer course, Modeling the Molecular World, Part I (or its predecessor, Genes, Schemes and Molecular Machines), students, and a research mentor.<br />
<br />
{{Clear}}<br />
=Qualification, Research, and Presentation Phases=<br />
Teams work to complete the three phases of the program:<br />
==<font color = 'blue'>Qualification Phase</font>==<br />
[[Image:Smart team 2.jpg|left|200px]]<br />
<br />
Students review basic concepts of protein structure and are introduced to the use of molecular visualization software (RasMol) to generate virtual images of proteins based on atomic coordinates obtained from the Protein Data Bank. Each Team then demonstrates their knowledge of these topics by designing and building a physical model of a protein that is currently in the news. This phase of the program ends with the Qualification Exam, a friendly yet competitive event in which Teams compete to demonstrate their expertise in all areas related to the physical modeling of molecular structures.<br />
<br />
{{Clear}}<br />
==<font color = 'blue'>Research and Model Design Phase</font>==<br />
[[Image:Smart Team photo 3.jpg|left|200px]]<br />
<br />
Qualified SMART Teams are then matched with a research scientist who is investigating a specific protein in their laboratory. The matching of Teams and mentors is accomplished through a “speed dating” activity in which all the Teams meet all of the potential mentors in a series of intense five-minute conversations. Compatible Teams and mentors are matched following this activity.<br />
<br />
Once matched, the Team visits the mentor’s laboratory and learns about their research project. The Team identifies a protein that is the focus of the lab’s research project, and then designs a physical model. During this research and design phase, the Team works closely with the mentor to create a physical model that will be useful as a “thinking tool” in the laboratory.<br />
<br />
{{Clear}}<br />
==<font color = 'blue'>Presentation Phase</font>==<br />
[[Image:Smart Team photo 4.jpg|left|200px]]<br />
<br />
Following the design and construction of the physical model, the Team continues to work with their mentor and teacher to develop a short oral presentation of their work for a lay audience, and a poster that is presented in a poster session within the scientific community. Some teams also present their posters to their local PTA or school board, or at a scientific research meeting, such as ASBMB or ASM.<br />
<br />
{{clear}}<br />
=SMART Team Proteopedia Pages=<br />
==<font color = 'blue'>Local SMART Teams</font>==<br />
===2008-2009===<br />
[[A_Physical_Model_of_the_β2-Adrenergic_Receptor|<font color = 'red'>A SMART Team Molecular Story</font><font color = 'black'> - Madison West High School Project of β2-Adrenergic Receptor</font>]]<br />
<br />
[[A_Physical_Model_of_the_Structure_of_GNNQQNY_from_Yeast_Prion_Sup35|<font color = 'red'>A SMART Team Molecular Story</font><font color = 'black'> - Community SMART Team of Southeast Wisconsin Project of GNNQQNY from Yeast Prion Sup35</font>]]<br />
===2009-2010===<br />
==<font color = 'blue'>HHMI SMART Teams</font>==<br />
===2008-2009===<br />
===2009-2010===<br />
==<font color = 'blue'>Remote SMART Teams</font>==<br />
===2007-2008===<br />
[[Tangible Models of Cdc42 Interacting With Intersectin]]<br />
===2008-2009===<br />
===2009-2010===</div>Kurt Gileshttps://proteopedia.org/index.php?title=Group:SMART:Teams&diff=952103Group:SMART:Teams2009-04-29T23:29:58Z<p>Kurt Giles: </p>
<hr />
<div>=Overview of the Program=<br />
[[Image:SMART Teams photo 1.jpg|left]]<br />
[[Image:Smart Teams photo 5.jpg|right|200px]]<br />
<br />
What do you get when you combine enthusiastic high school teachers and their students, scientists excited about their research, and Rapid Prototyping technology? <font color = 'red'>SMART</font> (<font color = 'red'>S</font>tudents <font color = 'red'>M</font>odeling <font color = 'red'>A R</font>esearch <font color = 'red'>T</font>opic) Teams! In this multi-faceted program, students develop teamwork as they delve into the molecular world, explore science as a process and not just a collection of facts, and work closely with a researcher to understand and model the structure-function relationship of a protein the researcher studies. After designing and building a model of the protein using Rapid Prototyping technology, SMART teams create an oral presentation explaining their work to a lay audience and a poster which is presented to a scientific audience.<br />
<br />
SMART Teams consist of a teacher who has participated in the Center for BioMolecular Modeling's summer course, Modeling the Molecular World, Part I (or its predecessor, Genes, Schemes and Molecular Machines), students, and a research mentor.<br />
<br />
{{Clear}}<br />
=Qualification, Research, and Presentation Phases=<br />
Teams work to complete the three phases of the program:<br />
==<font color = 'blue'>Qualification Phase</font>==<br />
[[Image:Smart team 2.jpg|left|200px]]<br />
<br />
Students review basic concepts of protein structure and are introduced to the use of molecular visualization software (RasMol) to generate virtual images of proteins based on atomic coordinates obtained from the Protein Data Bank. Each Team then demonstrates their knowledge of these topics by designing and building a physical model of a protein that is currently in the news. This phase of the program ends with the Qualification Exam, a friendly yet competitive event in which Teams compete to demonstrate their expertise in all areas related to the physical modeling of molecular structures.<br />
<br />
{{Clear}}<br />
==<font color = 'blue'>Research and Model Design Phase</font>==<br />
[[Image:Smart Team photo 3.jpg|left|200px]]<br />
<br />
Qualified SMART Teams are then matched with a research scientist who is investigating a specific protein in their laboratory. The matching of Teams and mentors is accomplished through a “speed dating” activity in which all the Teams meet all of the potential mentors in a series of intense five-minute conversations. Compatible Teams and mentors are matched following this activity.<br />
<br />
Once matched, the Team visits the mentor’s laboratory and learns about their research project. The Team identifies a protein that is the focus of the lab’s research project, and then designs a physical model. During this research and design phase, the Team works closely with the mentor to create a physical model that will be useful as a “thinking tool” in the laboratory.<br />
<br />
{{Clear}}<br />
==<font color = 'blue'>Presentation Phase</font>==<br />
[[Image:Smart Team photo 4.jpg|left|200px]]<br />
<br />
Following the design and construction of the physical model, the Team continues to work with their mentor and teacher to develop a short oral presentation of their work for a lay audience, and a poster that is presented in a poster session within the scientific community. Some teams also present their posters to their local PTA or school board, or at a scientific research meeting, such as ASBMB or ASM.<br />
<br />
{{clear}}<br />
=SMART Team Proteopedia Pages=<br />
==<font color = 'blue'>Local SMART Teams</font>==<br />
===2008-2009===<br />
[[A_Physical_Model_of_the_β2-Adrenergic_Receptor|<font color = 'red'>A SMART Team Molecular Story</font><font color = 'black'> - Madison West High School Project of β2-Adrenergic Receptor</font>]]<br />
<br />
[[A_Physical_Model_of_the_Structure_of_GNNQQNY_from_Yeast_Prion_Sup35|<font color = 'red'>A SMART Team Molecular Story</font><font color = 'black'> - Community SMART Team of Southeast Wisconsin Project of GNNQQNY from Yeast Prion Sup35</font>]]<br />
===2009-2010===<br />
==<font color = 'blue'>HHMI SMART Teams</font>==<br />
===2008-2009===<br />
===2009-2010===<br />
==<font color = 'blue'>Remote SMART Teams</font>==<br />
===2007-2008===<br />
[Tangible Models of Cdc42 Interacting With Intersectin]<br />
===2008-2009===<br />
===2009-2010===</div>Kurt Gileshttps://proteopedia.org/index.php?title=Group:SMART:Tangible_Models_of_Cdc42_Interacting_With_Intersectin&diff=952102Group:SMART:Tangible Models of Cdc42 Interacting With Intersectin2009-04-29T23:27:05Z<p>Kurt Giles: </p>
<hr />
<div>=='''<font color = 'red'>A Lincoln HS SMART Team Telling a Molecular Story</font><font color = 'black'></font>'''==<br />
[[Image:Lincoln Team 2008.JPG|left|360px]]<br />
<br />
<br />
<font color = 'red'><b>Abraham Lincoln High School, San Francisco, California</b></font><br />
:<b>Students</b> -- Cyndi He, Glen Huynh, Aissa Isana, Bradley Jann, Bradford Li, Yaqiao Li, Calvin Ng, Tiffany Saw, Elizaveta Sergeeva, Jacqueline Tam, Allison Trinh, Michelle Xie, Ellen Zhang<br />
:<b>Teacher</b> -- Julie Reis<br />
<br />
<br />
<font color = 'blue'><b>Mentors:</b></font><br />
:<b>UCSF Science and Health Education Partnership</b> -- Sabine Jeske<br />
:<b>UCSF/UCB Joint Graduate Group in Bioengineering</b> -- Angela Chau<br />
:<b>Institute for Neurodegenerative Diseases, UCSF</b> -- Kurt Giles<br />
:<b>Center for BioMolecular Modeling, Milwaukee School of Engineering</b> -- Shannondoah Colton<br />
<br />
<br />
{{clear}}<br />
<br />
='''<font color = 'black'>Abstract for Our Project</font>'''=<br />
<br />
==<font color = 'blue'>Abstract</font>==<br />
[[Image:Poster picture.jpg|right|380px]]<br />
<br />
:Information transfer within the cell relies upon signaling pathways made up of interacting proteins. Rho-family [[GTPase]]s are GTP-binding proteins, which function as molecular switches initially in the "off" state. Interactions with activators turn these GTPases "on" and they then interact with other proteins, leading to a variety of cellular behaviors such as directed movement and changes in cell shape.<br />
<br />
:Traditional methods for visualizing protein structures and interactions are often limited in the amount of information that can be conveyed in two dimensions. Using the rapid prototyping technology at the Milwaukee School of Engineering's Center for BioMolecular Modeling, we have built tangible 3D models of the Rho GTPase Cdc42 in complex with one of its activators. Our model shows the interaction of Cdc42 with the catalytic domains of intersectin, based upon the published crystal structure solved by Snyder, et al (PDB 1KI1, Nature Structural Biology 2002; 9(6): 468- 475). Along with computer visualization tools, tangible 3D models allow students and scientists alike to more fully explore the intricacies of protein interactions.<br />
<br />
{{clear}}<br />
<br />
==<font color = 'blue'>Cell Signaling and Cell Movement</font>==<br />
[[Image:Filopodia.jpg|left|250px]]<br />
<br />
<br />
:[[Cell signaling]] is how cells transmit information from the outside environment to inside the cell as well as how cells propagate messages within the cell. Transmembrane receptors at the cell surface detect environmental changes and pass the information on to intracellular signaling proteins. Proteins that make up signaling pathways pass along messages by interacting with each other.<br />
<br />
:Cell movement is integral for survival in both bacterial and eukaryotic cells. In eukaryotes, cells move by changing their [[cytoskeleton]]s to form [[actin]] structures like filopodia. These structures are formed in response to signals from outside of cells which are relayed throughout the cell using signaling pathways.<br />
<br />
{{clear}}<br />
<br />
==<font color = 'blue'>Why build a model?</font>==<br />
[[Image:Actual 3d models.JPG|right|150px]]<br />
<br />
<br />
:A 3-dimensional model generated by the polymer printing technology at the Center for BioMolecular Modeling greatly enhances our ability to visualize and explore Cdc42 and its interaction with Intersectin. The complex structures and shapes of these molecules can be appreciated more fully through seeing and touching a physical model. A tangible model can not only aid us in summarizing what we know but can also inspire us and other scientists to ask new questions and come up with new hypotheses about these molecules.<br />
<br />
{{clear}}<br />
<br />
='''<font color = 'black'>Cdc42: The GTPase</font>'''=<br />
[[Image:GDP to GTP.jpg|right|250px]]<br />
<br />
:Like other Rho GTPases, <scene name='SMART_Lincoln_2009/Cdc42_and_gdp/1'>Cdc42</scene> can exist in either the “Off” or “On” state. A [[guanosine diphosphate]] (GDP) in the nucleotide-binding pocket indicates the “Off” state, and a [[guanosine triphosphate]] (GTP) indicates the “On” state. The activation from the “Off” state to the “On” state is catalyzed by a [[guanine nucleotide exchange factor]] (GEF). Thee hydrolysis of GTP, which turns the GTPase off, is catalyzed by a GTPase activating protein called a GAP.<br />
<br />
:In addition to binding to a nucleotide (GDP or GTP), Cdc42 is usually found to be bound to a magnesium ion (Mg++), shown in magenta. The Mg++ sits near the nucleotide-binding pocket and helps to stabilize the Cdc42-nucleotide interaction.<br />
<br />
{{clear}}<br />
<br />
='''<font color = 'black'>Intersectin - The GEF</font>'''=<br />
<br />
:Intersectin is one of the activators of the GTPase Cdc42. It is a guanine nucleotide exchange factor (GEF) and turns on Cdc42 by catalyzing the exchange of GDP for GTP. Intersectin is a signaling protein that contains many domains, not all of which are shown here. The structure of the Cdc42/Intersectin complex was solved with the DH (residues 1229- 1439) and PH (residues 1440-1580) domains of Intersectin. Here, we focus only on the DH domain because the PH domain does not appear to come into any significant contact with Cdc42.<br />
<br />
{{clear}}<br />
<br />
='''<font color = 'black'>How Intersectin Activates Cdc42</font>'''=<br />
<br />
:<scene name='SMART_Lincoln_2009/Complex_intersectin_and_cdc42/1'>Cdc42/Intersectin Complex.</scene> The orientation of Alanine 59 is the highlight of Cdc42 activation by Intersectin. Alanine 59 causes the displacement of the Mg++ ion which in turn releases GDP from Cdc42’s binding pocket. Cdc42 is then able to accept a new nucleotide, specifically GTP, to become activated.<br />
<br />
<applet load='2rh1.pdb' size='350' frame='true' align='right' scene='SMART_Lincoln_2009/Complex_intersectin_and_cdc42/1'/><br />
<br />
<br />
1) <scene name='SMART_Lincoln_2009/Cdc42_and_gdp/1'>Cdc42</scene> (<font color = '#FFFF00'><b> yellow </b></font>) is off when GDP is in its binding pocket. <font color = '#FF1493'><b> Mg++ </b></font>is shown in magenta, <font color = '#00FF00'><b> Alanine 59 </b></font> in green, <font color = '#FFA500'><b>Switch 1</b></font> in light gold, and <font color = '#FF6600'><b>Switch 2</b></font> in dark orange. Brown depicts the residues interacting with <font color = '#00BFFF'><b>GDP</b></font> (<font color = '#8B4513'><b>Lys16 and Cys18</b></font>).<br />
<br />
<br />
2) <scene name='SMART_Lincoln_2009/Complex_intersectin_and_cdc42/1'>Intersectin</scene>(blue) binds to <font color = '#FFFF00'><b>Cdc42</b></font>, and its <font color = '#6A5ACD'><b>DH domain</b></font> interacts with the GTPase.<br />
<br />
<br />
3) Thee interaction causes conformational changes in <font color = '#FFA500'><b>Switch 1</b></font> and <font color = '#FF6600'><b>Switch 2</b></font> of Cdc42. <font color = '#FF0000'><b>Thr35</b></font> hydrogen bonds to a residue (<font color = '#802AAB'><b>Glu1244</b></font>) of the <font color = '#6A5ACD'><b>DH domain</b></font> of Intersectin. Most important is the noticeable change in the orientation of residue 59 (<font color = '#00FF00'><b>Ala59</b></font>). Its sidechain flips into the magnesium-binding pocket, causing the release of the <font color = '#FF1493'><b> Mg++ </b></font> ion and in turn the release of <font color = '#00BFFF'><b>GDP</b></font> from <font color = '#FFFF00'><b>Cdc42</b></font>.<br />
<br />
<br />
4) <font color = '#FF1493'><b> Mg++ </b></font> and <font color = '#00BFFF'><b>GDP</b></font> fall off from <font color = '#FFFF00'><b> Cdc42</b></font>. The nucleotide-binding pocket of <font color = '#FFFF00'><b>Cdc42</b></font> is now empty.<br />
<br />
<br />
5) Because the intracellular ratio of <font color = '#2F6E46'><b>GTP</b></font> to <font color = '#00BFFF'><b>GDP</b></font> is high, a <font color = '#2F6E46'><b>GTP</b></font> molecule (dark green) will float into the binding pocket of <font color = '#FFFF00'><b>Cdc42</b></font> and activate it.<br />
<br />
<br />
<br />
<br />
{{Clear}}<br />
<br />
==''<font color = 'black'>Animation: How Intersectin Activates Cdc42</font>''==<br />
<br />
<br />
<br />
{{Clear}}<br />
<br />
----<br />
<br />
=<font color = 'red'>MSOE Center for BioMolecular Modeling and SMART Teams</font>=<br />
[[Image:Center for BioMolecular Modeling Logo.jpg|left|200px]]<br />
[[Image:Smart Teams photo 5.jpg|right|120px]]<br />
<br />
<font color = 'red'>SMART Teams (S</font>tudents <font color = 'red'>M</font>odeling <font color = 'red'>A</font> <font color = 'red'>R</font>esearch <font color = 'red'>T</font>opic) is a science outreach program developed by the MSOE Center for BioMolecular Modeling. In this program, teams of high school students work with a local resarch lab to design and build a physical model of a protein that is being investigated by the lab. The goal of the SMART Team program is to introduce students to the real world of scince --- as it exists in a local research lab. The development of this program was supported by grants from the NIH-NCRR SEPA program (Science Education Partnership Award) and an HHMI Precollege Science Education Award. For more information about this program, visit the CBM web site at [http://www.rpc.msoe.edu/cbm www.rpc.msoe.edu/cbm] .</div>Kurt Gileshttps://proteopedia.org/index.php?title=Group:SMART:Lincoln_2009&diff=952101Group:SMART:Lincoln 20092009-04-29T23:26:22Z<p>Kurt Giles: SMART Lincoln 2009 moved to Tangible Models of Cdc42 Interacting With Intersectin: This was the 2008 team project. The new title represents the topic of the page</p>
<hr />
<div>#REDIRECT [[Tangible Models of Cdc42 Interacting With Intersectin]]</div>Kurt Gileshttps://proteopedia.org/index.php?title=Group:SMART:Tangible_Models_of_Cdc42_Interacting_With_Intersectin&diff=952100Group:SMART:Tangible Models of Cdc42 Interacting With Intersectin2009-04-29T23:26:22Z<p>Kurt Giles: SMART Lincoln 2009 moved to Tangible Models of Cdc42 Interacting With Intersectin: This was the 2008 team project. The new title represents the topic of the page</p>
<hr />
<div>='''<font color = 'black'> Tangible Models of Cdc42 Interacting With Intersectin </font>'''=<br />
<br />
=='''<font color = 'red'>A Lincoln HS SMART Team Telling a Molecular Story</font><font color = 'black'></font>'''==<br />
[[Image:Lincoln Team 2008.JPG|left|360px]]<br />
<br />
<br />
<font color = 'red'><b>Abraham Lincoln High School, San Francisco, California</b></font><br />
:<b>Students</b> -- Cyndi He, Glen Huynh, Aissa Isana, Bradley Jann, Bradford Li, Yaqiao Li, Calvin Ng, Tiffany Saw, Elizaveta Sergeeva, Jacqueline Tam, Allison Trinh, Michelle Xie, Ellen Zhang<br />
:<b>Teacher</b> -- Julie Reis<br />
<br />
<br />
<font color = 'blue'><b>Mentors:</b></font><br />
:<b>UCSF Science and Health Education Partnership</b> -- Sabine Jeske<br />
:<b>UCSF/UCB Joint Graduate Group in Bioengineering</b> -- Angela Chau<br />
:<b>Institute for Neurodegenerative Diseases, UCSF</b> -- Kurt Giles<br />
:<b>Center for BioMolecular Modeling, Milwaukee School of Engineering</b> -- Shannondoah Colton<br />
<br />
<br />
{{clear}}<br />
<br />
='''<font color = 'black'>Abstract for Our Project</font>'''=<br />
<br />
==<font color = 'blue'>Abstract</font>==<br />
[[Image:Poster picture.jpg|right|380px]]<br />
<br />
:Information transfer within the cell relies upon signaling pathways made up of interacting proteins. Rho-family [[GTPase]]s are GTP-binding proteins, which function as molecular switches initially in the "off" state. Interactions with activators turn these GTPases "on" and they then interact with other proteins, leading to a variety of cellular behaviors such as directed movement and changes in cell shape.<br />
<br />
:Traditional methods for visualizing protein structures and interactions are often limited in the amount of information that can be conveyed in two dimensions. Using the rapid prototyping technology at the Milwaukee School of Engineering's Center for BioMolecular Modeling, we have built tangible 3D models of the Rho GTPase Cdc42 in complex with one of its activators. Our model shows the interaction of Cdc42 with the catalytic domains of intersectin, based upon the published crystal structure solved by Snyder, et al (PDB 1KI1, Nature Structural Biology 2002; 9(6): 468- 475). Along with computer visualization tools, tangible 3D models allow students and scientists alike to more fully explore the intricacies of protein interactions.<br />
<br />
{{clear}}<br />
<br />
==<font color = 'blue'>Cell Signaling and Cell Movement</font>==<br />
[[Image:Filopodia.jpg|left|250px]]<br />
<br />
<br />
:[[Cell signaling]] is how cells transmit information from the outside environment to inside the cell as well as how cells propagate messages within the cell. Transmembrane receptors at the cell surface detect environmental changes and pass the information on to intracellular signaling proteins. Proteins that make up signaling pathways pass along messages by interacting with each other.<br />
<br />
:Cell movement is integral for survival in both bacterial and eukaryotic cells. In eukaryotes, cells move by changing their [[cytoskeleton]]s to form [[actin]] structures like filopodia. These structures are formed in response to signals from outside of cells which are relayed throughout the cell using signaling pathways.<br />
<br />
{{clear}}<br />
<br />
==<font color = 'blue'>Why build a model?</font>==<br />
[[Image:Actual 3d models.JPG|right|150px]]<br />
<br />
<br />
:A 3-dimensional model generated by the polymer printing technology at the Center for BioMolecular Modeling greatly enhances our ability to visualize and explore Cdc42 and its interaction with Intersectin. The complex structures and shapes of these molecules can be appreciated more fully through seeing and touching a physical model. A tangible model can not only aid us in summarizing what we know but can also inspire us and other scientists to ask new questions and come up with new hypotheses about these molecules.<br />
<br />
{{clear}}<br />
<br />
='''<font color = 'black'>Cdc42: The GTPase</font>'''=<br />
[[Image:GDP to GTP.jpg|right|250px]]<br />
<br />
:Like other Rho GTPases, <scene name='SMART_Lincoln_2009/Cdc42_and_gdp/1'>Cdc42</scene> can exist in either the “Off” or “On” state. A [[guanosine diphosphate]] (GDP) in the nucleotide-binding pocket indicates the “Off” state, and a [[guanosine triphosphate]] (GTP) indicates the “On” state. The activation from the “Off” state to the “On” state is catalyzed by a [[guanine nucleotide exchange factor]] (GEF). Thee hydrolysis of GTP, which turns the GTPase off, is catalyzed by a GTPase activating protein called a GAP.<br />
<br />
:In addition to binding to a nucleotide (GDP or GTP), Cdc42 is usually found to be bound to a magnesium ion (Mg++), shown in magenta. The Mg++ sits near the nucleotide-binding pocket and helps to stabilize the Cdc42-nucleotide interaction.<br />
<br />
{{clear}}<br />
<br />
='''<font color = 'black'>Intersectin - The GEF</font>'''=<br />
<br />
:Intersectin is one of the activators of the GTPase Cdc42. It is a guanine nucleotide exchange factor (GEF) and turns on Cdc42 by catalyzing the exchange of GDP for GTP. Intersectin is a signaling protein that contains many domains, not all of which are shown here. The structure of the Cdc42/Intersectin complex was solved with the DH (residues 1229- 1439) and PH (residues 1440-1580) domains of Intersectin. Here, we focus only on the DH domain because the PH domain does not appear to come into any significant contact with Cdc42.<br />
<br />
{{clear}}<br />
<br />
='''<font color = 'black'>How Intersectin Activates Cdc42</font>'''=<br />
<br />
:<scene name='SMART_Lincoln_2009/Complex_intersectin_and_cdc42/1'>Cdc42/Intersectin Complex.</scene> The orientation of Alanine 59 is the highlight of Cdc42 activation by Intersectin. Alanine 59 causes the displacement of the Mg++ ion which in turn releases GDP from Cdc42’s binding pocket. Cdc42 is then able to accept a new nucleotide, specifically GTP, to become activated.<br />
<br />
<applet load='2rh1.pdb' size='350' frame='true' align='right' scene='SMART_Lincoln_2009/Complex_intersectin_and_cdc42/1'/><br />
<br />
<br />
1) <scene name='SMART_Lincoln_2009/Cdc42_and_gdp/1'>Cdc42</scene> (<font color = '#FFFF00'><b> yellow </b></font>) is off when GDP is in its binding pocket. <font color = '#FF1493'><b> Mg++ </b></font>is shown in magenta, <font color = '#00FF00'><b> Alanine 59 </b></font> in green, <font color = '#FFA500'><b>Switch 1</b></font> in light gold, and <font color = '#FF6600'><b>Switch 2</b></font> in dark orange. Brown depicts the residues interacting with <font color = '#00BFFF'><b>GDP</b></font> (<font color = '#8B4513'><b>Lys16 and Cys18</b></font>).<br />
<br />
<br />
2) <scene name='SMART_Lincoln_2009/Complex_intersectin_and_cdc42/1'>Intersectin</scene>(blue) binds to <font color = '#FFFF00'><b>Cdc42</b></font>, and its <font color = '#6A5ACD'><b>DH domain</b></font> interacts with the GTPase.<br />
<br />
<br />
3) Thee interaction causes conformational changes in <font color = '#FFA500'><b>Switch 1</b></font> and <font color = '#FF6600'><b>Switch 2</b></font> of Cdc42. <font color = '#FF0000'><b>Thr35</b></font> hydrogen bonds to a residue (<font color = '#802AAB'><b>Glu1244</b></font>) of the <font color = '#6A5ACD'><b>DH domain</b></font> of Intersectin. Most important is the noticeable change in the orientation of residue 59 (<font color = '#00FF00'><b>Ala59</b></font>). Its sidechain flips into the magnesium-binding pocket, causing the release of the <font color = '#FF1493'><b> Mg++ </b></font> ion and in turn the release of <font color = '#00BFFF'><b>GDP</b></font> from <font color = '#FFFF00'><b>Cdc42</b></font>.<br />
<br />
<br />
4) <font color = '#FF1493'><b> Mg++ </b></font> and <font color = '#00BFFF'><b>GDP</b></font> fall off from <font color = '#FFFF00'><b> Cdc42</b></font>. The nucleotide-binding pocket of <font color = '#FFFF00'><b>Cdc42</b></font> is now empty.<br />
<br />
<br />
5) Because the intracellular ratio of <font color = '#2F6E46'><b>GTP</b></font> to <font color = '#00BFFF'><b>GDP</b></font> is high, a <font color = '#2F6E46'><b>GTP</b></font> molecule (dark green) will float into the binding pocket of <font color = '#FFFF00'><b>Cdc42</b></font> and activate it.<br />
<br />
<br />
<br />
<br />
{{Clear}}<br />
<br />
==''<font color = 'black'>Animation: How Intersectin Activates Cdc42</font>''==<br />
<br />
<br />
<br />
{{Clear}}<br />
<br />
----<br />
<br />
=<font color = 'red'>MSOE Center for BioMolecular Modeling and SMART Teams</font>=<br />
[[Image:Center for BioMolecular Modeling Logo.jpg|left|200px]]<br />
[[Image:Smart Teams photo 5.jpg|right|120px]]<br />
<br />
<font color = 'red'>SMART Teams (S</font>tudents <font color = 'red'>M</font>odeling <font color = 'red'>A</font> <font color = 'red'>R</font>esearch <font color = 'red'>T</font>opic) is a science outreach program developed by the MSOE Center for BioMolecular Modeling. In this program, teams of high school students work with a local resarch lab to design and build a physical model of a protein that is being investigated by the lab. The goal of the SMART Team program is to introduce students to the real world of scince --- as it exists in a local research lab. The development of this program was supported by grants from the NIH-NCRR SEPA program (Science Education Partnership Award) and an HHMI Precollege Science Education Award. For more information about this program, visit the CBM web site at [http://www.rpc.msoe.edu/cbm www.rpc.msoe.edu/cbm] .</div>Kurt Gileshttps://proteopedia.org/index.php?title=Sandbox1&diff=822008Sandbox12009-02-03T01:46:53Z<p>Kurt Giles: </p>
<hr />
<div>Human Glutamine Synthetase Tertiary Structure: Pfam domains<br />
<br />
The active site of Glutamine synthetase is the result of the interactions between two adjacent subunits.<br />
Each Subunits contains two two ends, the C-terminus and the N-terminus. The Glutamine synthetase beta grasp domain(N-terminus), and the Glutamine synthetase catalytic domain (the C-terminus). In order to stabilize the molecule, the two domains are involved in the Van Der Walls , Hydrogen . The Beta Grasp domain interact with the C-terminus of the next subunit.the two domains are proceeded by a meander of 3-24 residues that link the chains in the proteins core. <br />
<br />
Beta Grasp domain (N-terminus) <br />
-comprised of residues 43-123<br />
-binds glutamate, ammonia, and ATP<br />
<show protein alignment image><br />
<show structure of the domain in viewer><br />
<br />
Catalytic domain (C-terminus)<br />
-comprised of residues 129-382<br />
-how it functions is not described, more research is necessary here<br />
<br />
<show alignment image><br />
<show structure of the domain in viewer><br />
<br />
Active site<br />
-there are 10 active sites in the decamer of the protein, each formed from the beta grasp domain of one chain and the catalytic domain of the neighboring chain. <br />
<show relation between chains, domains, and active sites with viewer><br />
-describe visually the important aspects of the active site<br />
<show active site and ligands relationship, may need multiple scenes><br />
<br />
----</div>Kurt Gileshttps://proteopedia.org/index.php?title=SandboxLiza&diff=822007SandboxLiza2009-02-03T01:44:06Z<p>Kurt Giles: New page: ==This is a placeholder== This is a placeholder text to help you get started in placing a Jmol applet on your page. At any time, click "Show Preview" at the bottom of this page to see how...</p>
<hr />
<div>==This is a placeholder==<br />
This is a placeholder text to help you get started in <br />
placing a Jmol applet on your page. At any time, click<br />
"Show Preview" at the bottom of this page to see how it goes.<br />
<br />
Replace the PDB id after the STRUCTURE_ and after PDB= to load <br />
and display another structure.<br />
<br />
{{STRUCTURE_3cin | PDB=3cin | SCENE= }}<br />
<br />
<br />
<font color = 'red'>SMART Teams (S</font>tudents <font color = 'red'>M</font>odeling <font color = 'red'>A</font> <font color = 'red'>R</font>esearch <font color = 'red'>T</font>opic) is a science outreach program developed by the MSOE Center for BioMolecular Modeling. In this program, teams of high school students work with a local resarch lab to design and build a physical model of a protein that is being investigated by the lab. The goal of the SMART Team program is to introduce students to the real world of scince --- as it exists in a local research lab. The development of this program was supported by grants from the NIH-NCRR SEPA program (Science Education Partnership Award) and an HHMI Precollege Science Education Award. For more information about this program, visit the CBM web site at [http://www.rpc.msoe.edu/cbm www.rpc.msoe.edu/cbm] .</div>Kurt Gileshttps://proteopedia.org/index.php?title=Sandbox1&diff=822006Sandbox12009-02-03T01:24:21Z<p>Kurt Giles: </p>
<hr />
<div>Human Glutamine Synthetase Tertiary Structure: Pfam domains<br />
<br />
The active site of Glutamine synthetase is the result of the interactions between two adjacent subunits.<br />
Each Subunits contains two two ends, the C-terminus and the N-terminus. The Glutamine synthetase beta grasp domain(N-terminus), and the Glutamine synthetase catalytic domain (the C-terminus). In order to stabilize the molecule, the two domains are involved in the Van Der Walls , Hydrogen . The Beta Grasp domain interact with the C-terminus of the next subunit.the two domains are proceeded by a meander of 3-24 residues that link the chains in the proteins core. <br />
<br />
Beta Grasp domain (N-terminus) <br />
-comprised of residues 43-123<br />
-binds glutamate, ammonia, and ATP<br />
<show protein alignment image><br />
<show structure of the domain in viewer><br />
<br />
Catalytic domain (C-terminus)<br />
-comprised of residues 129-382<br />
-how it functions is not described, more research is necessary here<br />
<br />
<show alignment image><br />
<show structure of the domain in viewer><br />
<br />
Active site<br />
-there are 10 active sites in the decamer of the protein, each formed from the beta grasp domain of one chain and the catalytic domain of the neighboring chain. <br />
<show relation between chains, domains, and active sites with viewer><br />
-describe visually the important aspects of the active site<br />
<show active site and ligands relationship, may need multiple scenes><br />
<br />
----<br />
<br />
Trying to insert a movie: [[Image:406849ai1.mov]]</div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=822004Prion protein2009-02-03T01:09:54Z<p>Kurt Giles: </p>
<hr />
<div>The [[prion protein]] (PrP) is a cell surface glycoprotein, which can exist in two alternatively folded conformations: a cellular isoform denoted (PrP<sup>C</sup>) and a disease associated isoform termed PrP<sup>Sc</sup>. <br />
<br />
==Prion diseases==<br />
The naturally ocuring prion diseases include [http://en.wikipedia.org/wiki/Creutzfeldt-Jakob_disease Creutzfeldt-Jakob disease] (CJD) in people, [http://en.wikipedia.org/wiki/Bovine_spongiform_encephalopathy bovine spongiform encephalopathy] (BSE) commonly known as "mad cow" disease, [http://en.wikipedia.org/wiki/Scrapie scrapie] in sheep and goats, and [http://en.wikipedia.org/wiki/Chronic_wasting_disease chronic wasting disease] in deer. In all cases ''post mortem'' analysis of brain tissue is characterized by aggregates of PrP<sup>Sc</sup>.<br />
The sporadic, genetic and infectious etiologies of prion diseases can be explained by a simple protein-based model in which PrP<sup>C</sup> is converted into PrP<sup>Sc</sup> that in turn initiates an autocatalytic refolding cascade of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
In sporadic prion disease, the spontaneous refolding or misfolding of PrP<sup>C</sup> into PrP<sup>Sc</sup> initiates the cascade. In genetic prion diseases, point mutations in PrP make this structural transition more likely to occur than in the ''wild type'' protein. Infectious etiology is explained by introduction of exogenous PrP<sup>Sc</sup> which then initiates refolding of endogenous PrP<sup>C</sup>.<br />
<br />
==Structure of PrP<sup>C</sup>==<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE=Prion_protein/Cartoon/4 }}<br />
PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230, containing three α-helices and two short <scene name='Prion_protein/Cartoon/3'>β-strands</scene>. A <scene name='Prion_protein/1hjm_disulfide_bond/4'>single disulfide bond</scene> connects the middle of helices 2 and 3. The presence of the N-terminal region has little impact on the structure of the C-terminal domain <ref>Zahn, R ''et al.'' (2000) NMR solution structure of the human prion protein ''Proc. Natl. Acad. Sci. USA'' '''97''', 145-150</ref>. The structure of PrP<sup>C</sup> is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians<ref>Calzolai, L ''et al.'' (2005) Prion protein NMR structures of chicken, turtle, and frog ''Proc. Natl. Acad. Sci. USA'' '''102''', 651-655</ref>.<br />
The vast majority of structures have been determined by NMR spectroscopy, but two structures have been reported by X-ray crystallography. In sheep PrP, the X-ray structure is similar to those determined by NMR spectroscopy, however in human PrP, the X-ray structure is a dimer in which helix 3 is swapped between monomers, and the disulphide bond is rearranged to be intermolecular between the dimer subunits.<br />
<br />
<br />
==Models of PrP<sup>Sc</sup> structure==<br />
Fourier transform infrared (FTIR) spectroscopy, and circular dichroism (CD) studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><ref>Pan, KM ''et al.'' (1993) Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins ''Proc. Natl. Acad. Sci. USA'' '''90''', 10962-10966</ref>. There are a number of technical obstacles in determining the atomic resolution structure of PrP<sup>Sc</sup>, and the most detailed information to date has been obtained by electron microscopy of 2D crystals<ref>Wille H ''et al.'' (2002) Structural studies of the scrapie prion protein by electron crystallography ''Proc. Natl. Acad. Sci. USA'' '''99''', 3563-3568</ref>. Analysis of 2D crystals binding specific heavy metal ions, and of redacted constructs of PrP, provide a basis for structural modeling.<br />
A model the N-terminal region and part of the C-terminal domain, up to the disulphide bond, refolds into a β-helical structure<ref>Govaerts C ''et al.'' (2004) Ecidence for assembly of prions with left-handed β-helices into trimers ''Proc. Natl. Acad. Sci. USA'' '''101''', 8342-8347</ref>. Support for this β-helical model comes from the structure of the fungal prion Het-s ([[2rnm]]).<br />
<br />
==Prion strains==<br />
The phenomenon of prion strains (disease subtypes with specific clinical, biochemical and neuropathological features, replicating with high fidelity) was initially difficult to equate with the "protein only" hypothesis of prion diseases. However, there is now evidence from a range if studies suggesting that strains are enciphered in the structure of PrP<sup>Sc</sup>. One potential mechanism for this is alternate threading of the β-helix.<br />
<br />
==Hot Spots in PrP<sup>C</sup> for pathogenic conversion==<br />
There are several <scene name='Prion_protein/Prion_point_mutations/1'>point mutations associated with known human prion diseases</scene> (P102L, P105L, A117V, M129V, G131V, Y145Stop, R148H, Q160Stop, D178N, V180I, T183A, H187R, T188R, E196K, F198S, E200K, D202N, V203I, R208H, V210I, E211Q, Q212P, and Q217R). <br />
The pathogenic conversion process from PrP<sup>C</sup> to PrP<sup>Sc</sup> could be related to the thermal stability of PrP<sup>C</sup> <ref>Kuwata, K. ''et al.'' (2007) Hot spots in prion protein for pathogenic conversion ''Proc. Natl. Acad. Sci. USA'' '''104''', 11921–11926</ref>, since the mutations related to familial forms of the prion diseases are rather concentrated in helices 2 and 3, and the thermodynamical stability profile shows that diverse residues in helices 2 and 3 are less stable <ref>Kuwata, K. ''et al.'' (2002) Locally disordered conformer of the hamster prion protein: a crucial intermediate to PrP<sup>Sc</sup> ''Biochemistry '' '''41''', 12277–12283</ref>.<br />
Moreover, the conversion might also be related with the global conformational fluctuation of PrP<sup>C</sup>, as a Carr–Purcell–Meiboom–Gill relaxation–dispersion<br />
study revealed that slow fluctuation on a time scale of microseconds to milliseconds occurs, again, in helices 2 and 3<ref>Kuwata, K. ''et al.'' (2004) Slow conformational dynamics in the hamster prion protein ''Biochemistry'' '''43''', 4439-4446</ref>,<ref>Korzhnev, D.M. ''et al.'' (2004) Low-populated folding intermediates of Fyn SH3 characterized by relaxation dispersion NMR ''Nature'' '''430''', 586-590</ref>.<br />
<br />
==Selected PrP structures==<br />
All structures determined by NMR spectroscopy unless otherwise specified<br />
===Human PrP===<br />
* [[1qlx]] Residues 23-230 <br />
* [[1qm0]] Residues 90-230 <br />
* [[1qm2]] Residues 121-230 <br />
* [[1i4m]] Determined by X-ray crystallography<br />
* [[1fkc]] E200K mutant (genetic prion disease) <br />
<br />
===PrP from other species===<br />
* [[1xyx]] Mouse PrP <br />
* [[1b10]] Syrian hamster PrP<br />
* [[1dwy]] Cow PrP<br />
* [[1uw3]] Sheep PrP (determined by X-ray crystallography)<br />
* [[1xu0]] Frog PrP<br />
* [[1u3m]] Chicken PrP<br />
* [[1u5l]] Turtle PrP<br />
<br />
==References== <br />
<references/></div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=822003Prion protein2009-02-03T01:08:49Z<p>Kurt Giles: </p>
<hr />
<div>The [[prion protein]] (PrP) is a cell surface glycoprotein, which can exist in two alternatively folded conformations: a cellular isoform denoted (PrP<sup>C</sup>) and a disease associated isoform termed PrP<sup>Sc</sup>. <br />
<br />
==Prion diseases==<br />
The naturally ocuring prion diseases include [http://en.wikipedia.org/wiki/Creutzfeldt-Jakob_disease Creutzfeldt-Jakob disease] (CJD) in people, [http://en.wikipedia.org/wiki/Bovine_spongiform_encephalopathy bovine spongiform encephalopathy] (BSE) commonly known as "mad cow" disease, [http://en.wikipedia.org/wiki/Scrapie scrapie] in sheep and goats, and [http://en.wikipedia.org/wiki/Chronic_wasting_disease chronic wasting disease] in deer. In all cases ''post mortem'' analysis of brain tissue is characterized by aggregates of PrP<sup>Sc</sup>.<br />
The sporadic, genetic and infectious etiologies of prion diseases can be explained by a simple protein-based model in which PrP<sup>C</sup> is converted into PrP<sup>Sc</sup> that in turn initiates an autocatalytic refolding cascade of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
In sporadic prion disease, the spontaneous refolding or misfolding of PrP<sup>C</sup> into PrP<sup>Sc</sup> initiates the cascade. In genetic prion diseases, point mutations in PrP make this structural transition more likely to occur than in the ''wild type'' protein. Infectious etiology is explained by introduction of exogenous PrP<sup>Sc</sup> which then initiates refolding of endogenous PrP<sup>C</sup>.<br />
<br />
==Structure of PrP<sup>C</sup>==<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE=Prion_protein/Cartoon/4 }}<br />
PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230, containing three α-helices and two short <scene name='Prion_protein/Cartoon/3'>β-strands</scene>. A <scene name='Prion_protein/1hjm_disulfide_bond/4'>single disulfide bond</scene> connects the middle of helices 2 and 3. The presence of the N-terminal region has little impact on the structure of the C-terminal domain <ref>Zahn, R ''et al.'' (2000) NMR solution structure of the human prion protein ''Proc. Natl. Acad. Sci. USA'' '''97''', 145-150</ref>. The structure of PrP<sup>C</sup> is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians<ref>Calzolai, L ''et al.'' (2005) Prion protein NMR structures of chicken, turtle, and frog ''Proc. Natl. Acad. Sci. USA'' '''102''', 651-655</ref>.<br />
The vast majority of structures have been determined by NMR spectroscopy, but two structures have been reported by X-ray crystallography. In sheep PrP, the X-ray structure is similar to those determined by NMR spectroscopy, however in human PrP, the X-ray structure is a dimer in which helix 3 is swapped between monomers, and the disulphide bond is rearranged to be intermolecular between the dimer subunits.<br />
<scene name='Prion_protein/Green_n-term/1'>test green part</scene><br />
<br />
==Models of PrP<sup>Sc</sup> structure==<br />
Fourier transform infrared (FTIR) spectroscopy, and circular dichroism (CD) studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><ref>Pan, KM ''et al.'' (1993) Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins ''Proc. Natl. Acad. Sci. USA'' '''90''', 10962-10966</ref>. There are a number of technical obstacles in determining the atomic resolution structure of PrP<sup>Sc</sup>, and the most detailed information to date has been obtained by electron microscopy of 2D crystals<ref>Wille H ''et al.'' (2002) Structural studies of the scrapie prion protein by electron crystallography ''Proc. Natl. Acad. Sci. USA'' '''99''', 3563-3568</ref>. Analysis of 2D crystals binding specific heavy metal ions, and of redacted constructs of PrP, provide a basis for structural modeling.<br />
A model the N-terminal region and part of the C-terminal domain, up to the disulphide bond, refolds into a β-helical structure<ref>Govaerts C ''et al.'' (2004) Ecidence for assembly of prions with left-handed β-helices into trimers ''Proc. Natl. Acad. Sci. USA'' '''101''', 8342-8347</ref>. Support for this β-helical model comes from the structure of the fungal prion Het-s ([[2rnm]]).<br />
<br />
==Prion strains==<br />
The phenomenon of prion strains (disease subtypes with specific clinical, biochemical and neuropathological features, replicating with high fidelity) was initially difficult to equate with the "protein only" hypothesis of prion diseases. However, there is now evidence from a range if studies suggesting that strains are enciphered in the structure of PrP<sup>Sc</sup>. One potential mechanism for this is alternate threading of the β-helix.<br />
<br />
==Hot Spots in PrP<sup>C</sup> for pathogenic conversion==<br />
There are several <scene name='Prion_protein/Prion_point_mutations/1'>point mutations associated with known human prion diseases</scene> (P102L, P105L, A117V, M129V, G131V, Y145Stop, R148H, Q160Stop, D178N, V180I, T183A, H187R, T188R, E196K, F198S, E200K, D202N, V203I, R208H, V210I, E211Q, Q212P, and Q217R). <br />
The pathogenic conversion process from PrP<sup>C</sup> to PrP<sup>Sc</sup> could be related to the thermal stability of PrP<sup>C</sup> <ref>Kuwata, K. ''et al.'' (2007) Hot spots in prion protein for pathogenic conversion ''Proc. Natl. Acad. Sci. USA'' '''104''', 11921–11926</ref>, since the mutations related to familial forms of the prion diseases are rather concentrated in helices 2 and 3, and the thermodynamical stability profile shows that diverse residues in helices 2 and 3 are less stable <ref>Kuwata, K. ''et al.'' (2002) Locally disordered conformer of the hamster prion protein: a crucial intermediate to PrP<sup>Sc</sup> ''Biochemistry '' '''41''', 12277–12283</ref>.<br />
Moreover, the conversion might also be related with the global conformational fluctuation of PrP<sup>C</sup>, as a Carr–Purcell–Meiboom–Gill relaxation–dispersion<br />
study revealed that slow fluctuation on a time scale of microseconds to milliseconds occurs, again, in helices 2 and 3<ref>Kuwata, K. ''et al.'' (2004) Slow conformational dynamics in the hamster prion protein ''Biochemistry'' '''43''', 4439-4446</ref>,<ref>Korzhnev, D.M. ''et al.'' (2004) Low-populated folding intermediates of Fyn SH3 characterized by relaxation dispersion NMR ''Nature'' '''430''', 586-590</ref>.<br />
<br />
==Selected PrP structures==<br />
All structures determined by NMR spectroscopy unless otherwise specified<br />
===Human PrP===<br />
* [[1qlx]] Residues 23-230 <br />
* [[1qm0]] Residues 90-230 <br />
* [[1qm2]] Residues 121-230 <br />
* [[1i4m]] Determined by X-ray crystallography<br />
* [[1fkc]] E200K mutant (genetic prion disease) <br />
<br />
===PrP from other species===<br />
* [[1xyx]] Mouse PrP <br />
* [[1b10]] Syrian hamster PrP<br />
* [[1dwy]] Cow PrP<br />
* [[1uw3]] Sheep PrP (determined by X-ray crystallography)<br />
* [[1xu0]] Frog PrP<br />
* [[1u3m]] Chicken PrP<br />
* [[1u5l]] Turtle PrP<br />
<br />
==References== <br />
<references/></div>Kurt Gileshttps://proteopedia.org/index.php?title=Doppel&diff=810987Doppel2008-12-22T04:27:52Z<p>Kurt Giles: </p>
<hr />
<div>[[Doppel]] (Dpl), named for '''''do'''wnstream '''p'''rion '''p'''rotein-like''<ref>Moore, R ''et al.'' (1999) Ataxia in Prion Protein (PrP)-deficient mice is associated with upregulation of the novel PrP-like protein Doppel ''J. Mol. Biol.'' '''292''', 797-817</ref>, is a homolog of the [[prion protein]] (PrP). It is a cell surface glycoprotein.<br />
<br />
==Structure of Dpl==<br />
<br />
{{STRUCTURE_1lg4 | PDB=1lg4 | SCENE=Doppel/Cartoon/1 }}<br />
Dpl has the same fold as the C-terminal domain [[PrP]], with three alpha helices and two short beta strands<ref>Mo H ''et al.'' (2001) ''Proc. Natl. Acad. Sci. USA'' '''98''',2352-7</ref>. However Dpl differs from [[PrP]] in two important respects: the second helix of Dpl has a pronounced kink in it, and Dpl also contains <scene name='Doppel/Disulfide_bonds/1'>two disulphide bonds</scene>.<br />
<br />
The structure mutant PrP with the additional disulphide bond was also determined <ref>Zahn R ''et al.'' (2003) NMR structure of a variant human prion protein with two disulfide bridges '' J. Mol. Biol.'' '''326''', 225-34.</ref><br />
<br />
<br />
==Related structures==<br />
* [[1z65]] Mouse Dpl residues 1-30<br />
* [[1lg4]] Human Dpl residues 24-152<br />
* [[1i17]] Mouse Dpl residues 51-157<br />
* [[1h0l]] Human PrP residues 121-230, with an additional disulphide bond analogous to the homolog [[Doppel]]<br />
<br />
<br />
==References==<br />
<references/></div>Kurt Gileshttps://proteopedia.org/index.php?title=File:1I17_1.pdb&diff=810978File:1I17 1.pdb2008-12-22T04:10:14Z<p>Kurt Giles: Model 1 of 1i17</p>
<hr />
<div>Model 1 of 1i17</div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=810976Prion protein2008-12-22T03:48:22Z<p>Kurt Giles: </p>
<hr />
<div>The [[prion protein]] (PrP) is a cell surface glycoprotein, which can exist in two alternatively folded conformations: a cellular isoform denoted (PrP<sup>C</sup>) and a disease associated isoform termed PrP<sup>Sc</sup>. <br />
<br />
==Prion diseases==<br />
The naturally ocuring prion diseases include [http://en.wikipedia.org/wiki/Creutzfeldt-Jakob_disease Creutzfeldt-Jakob disease] (CJD) in people, [http://en.wikipedia.org/wiki/Bovine_spongiform_encephalopathy bovine spongiform encephalopathy] (BSE) commonly known as "mad cow" disease, [http://en.wikipedia.org/wiki/Scrapie scrapie] in sheep and goats, and [http://en.wikipedia.org/wiki/Chronic_wasting_disease chronic wasting disease] in deer. In all cases ''post mortem'' analysis of brain tissue is characterized by aggregates of PrP<sup>Sc</sup>.<br />
The sporadic, genetic and infectious etiologies of prion diseases can be explained by a simple protein-based model in which PrP<sup>C</sup> is converted into PrP<sup>Sc</sup> that in turn initiates an autocatalytic refolding cascade of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
In sporadic prion disease, the spontaneous refolding or misfolding of PrP<sup>C</sup> into PrP<sup>Sc</sup> initiates the cascade. In genetic prion diseases, point mutations in PrP make this structural transition more likely to occur than in the ''wild type'' protein. Infectious etiology is explained by introduction of exogenous PrP<sup>Sc</sup> which then initiates refolding of endogenous PrP<sup>C</sup>.<br />
<br />
==Structure of PrP<sup>C</sup>==<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE=Prion_protein/Cartoon/4 }}<br />
PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230, containing three α-helices and two short <scene name='Prion_protein/Cartoon/3'>β-strands</scene>. A <scene name='Prion_protein/1hjm_disulfide_bond/4'>single disulfide bond</scene> connects the middle of helices 2 and 3. The presence of the N-terminal region has little impact on the structure of the C-terminal domain <ref>Zahn, R ''et al.'' (2000) NMR solution structure of the human prion protein ''Proc. Natl. Acad. Sci. USA'' '''97''', 145-150</ref>. The structure of PrP<sup>C</sup> is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians<ref>Calzolai, L ''et al.'' (2005) Prion protein NMR structures of chicken, turtle, and frog ''Proc. Natl. Acad. Sci. USA'' '''102''', 651-655</ref>.<br />
The vast majority of structures have been determined by NMR spectroscopy, but two structures have been reported by X-ray crystallography. In sheep PrP, the X-ray structure is similar to those determined by NMR spectroscopy, however in human PrP, the X-ray structure is a dimer in which helix 3 is swapped between monomers, and the disulphide bond is rearranged to be intermolecular between the dimer subunits.<br />
<br />
==Models of PrP<sup>Sc</sup> structure==<br />
Fourier transform infrared (FTIR) spectroscopy, and circular dichroism (CD) studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><ref>Pan, KM ''et al.'' (1993) Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins ''Proc. Natl. Acad. Sci. USA'' '''90''', 10962-10966</ref>. There are a number of technical obstacles in determining the atomic resolution structure of PrP<sup>Sc</sup>, and the most detailed information to date has been obtained by electron microscopy of 2D crystals<ref>Wille H ''et al.'' (2002) Structural studies of the scrapie prion protein by electron crystallography ''Proc. Natl. Acad. Sci. USA'' '''99''', 3563-3568</ref>. Analysis of 2D crystals binding specific heavy metal ions, and of redacted constructs of PrP, provide a basis for structural modeling.<br />
A model the N-terminal region and part of the C-terminal domain, up to the disulphide bond, refolds into a β-helical structure<ref>Govaerts C ''et al.'' (2004) Ecidence for assembly of prions with left-handed β-helices into trimers ''Proc. Natl. Acad. Sci. USA'' '''101''', 8342-8347</ref>. Support for this β-helical model comes from the structure of the fungal prion Het-s ([[2rnm]]).<br />
<br />
==Prion strains==<br />
The phenomenon of prion strains (disease subtypes with specific clinical, biochemical and neuropathological features, replicating with high fidelity) was initially difficult to equate with the "protein only" hypothesis of prion diseases. However, there is now evidence from a range if studies suggesting that strains are enciphered in the structure of PrP<sup>Sc</sup>. One potential mechanism for this is alternate threading of the β-helix.<br />
<br />
==Selected PrP structures==<br />
All structures determined by NMR spectroscopy unless otherwise specified<br />
===Human PrP===<br />
* [[1qlx]] Residues 23-230 <br />
* [[1qm0]] Residues 90-230 <br />
* [[1qm2]] Residues 121-230 <br />
* [[1i4m]] Determined by X-ray crystallography<br />
* [[1fkc]] E200K mutant (genetic prion disease) <br />
<br />
===PrP from other species===<br />
* [[1xyx]] Mouse PrP <br />
* [[1b10]] Syrian hamster PrP<br />
* [[1dwy]] Cow PrP<br />
* [[1uw3]] Sheep PrP (determined by X-ray crystallography)<br />
* [[1xu0]] Frog PrP<br />
* [[1u3m]] Chicken PrP<br />
* [[1u5l]] Turtle PrP<br />
<br />
==References== <br />
<references/></div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=810889Prion protein2008-12-21T06:58:44Z<p>Kurt Giles: </p>
<hr />
<div>The [[prion protein]] (PrP) is a cell surface glycoprotein, which can exist in two alternatively folded conformations: a cellular isoform denoted (PrP<sup>C</sup>) and a disease associated isoform termed PrP<sup>Sc</sup>. <br />
<br />
==Prion diseases==<br />
The naturally ocuring prion diseases include [http://en.wikipedia.org/wiki/Creutzfeldt-Jakob_disease Creutzfeldt-Jakob disease] (CJD) in people, [http://en.wikipedia.org/wiki/Bovine_spongiform_encephalopathy bovine spongiform encephalopathy] (BSE) commonly known as "mad cow" disease, [http://en.wikipedia.org/wiki/Scrapie scrapie] in sheep and goats, and [http://en.wikipedia.org/wiki/Chronic_wasting_disease chronic wasting disease] in deer. In all cases ''post mortem'' analysis of brain tissue is characterized by aggregates of PrP<sup>Sc</sup>.<br />
The sporadic, genetic and infectious etiologies of prion diseases can be explained by a simple protein-based model in which PrP<sup>C</sup> is converted into PrP<sup>Sc</sup> that in turn initiates an autocatalytic refolding cascade of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
In sporadic prion disease, the spontaneous refolding or misfolding of PrP<sup>C</sup> into PrP<sup>Sc</sup> initiates the cascade. In genetic prion diseases, point mutations in PrP make this structural transition more likely to occur than in the ''wild type'' protein. Infectious etiology is explained by introduction of exogenous PrP<sup>Sc</sup> which then initiates refolding of endogenous PrP<sup>C</sup>.<br />
<br />
==Structure of PrP<sup>C</sup>==<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE=Prion_protein/Cartoon/1 }}<br />
PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230, containing three α-helices and two short β-strands. A <scene name='Prion_protein/1hjm_disulfide_bond/2'>single disulfide bond</scene> connects the middle of helices 2 and 3. The presence of the N-terminal region has little impact on the structure of the C-terminal domain <ref>Zahn, R ''et al.'' (2000) NMR solution structure of the human prion protein ''Proc. Natl. Acad. Sci. USA'' '''97''', 145-150</ref>. The structure of PrP<sup>C</sup> is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians<ref>Calzolai, L ''et al.'' (2005) Prion protein NMR structures of chicken, turtle, and frog ''Proc. Natl. Acad. Sci. USA'' '''102''', 651-655</ref>.<br />
The vast majority of structures have been determined by NMR spectroscopy, but two structures have been reported by X-ray crystallography. In sheep PrP, the X-ray structure is similar to those determined by NMR spectroscopy, however in human PrP, the X-ray structure is a dimer in which helix 3 is swapped between monomers, and the disulphide bond is rearranged to be intermolecular between the dimer subunits.<br />
<br />
==Models of PrP<sup>Sc</sup> structure==<br />
Fourier transform infrared (FTIR) spectroscopy, and circular dichroism (CD) studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><ref>Pan, KM ''et al.'' (1993) Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins ''Proc. Natl. Acad. Sci. USA'' '''90''', 10962-10966</ref>. There are a number of technical obstacles in determining the atomic resolution structure of PrP<sup>Sc</sup>, and the most detailed information to date has been obtained by electron microscopy of 2D crystals<ref>Wille H ''et al.'' (2002) Structural studies of the scrapie prion protein by electron crystallography ''Proc. Natl. Acad. Sci. USA'' '''99''', 3563-3568</ref>. Analysis of 2D crystals binding specific heavy metal ions, and of redacted constructs of PrP, provide a basis for structural modeling.<br />
A model the N-terminal region and part of the C-terminal domain, up to the disulphide bond, refolds into a β-helical structure<ref>Govaerts C ''et al.'' (2004) Ecidence for assembly of prions with left-handed β-helices into trimers ''Proc. Natl. Acad. Sci. USA'' '''101''', 8342-8347</ref>. Support for this β-helical model comes from the structure of the fungal prion Het-s ([[2rnm]]).<br />
<br />
==Prion strains==<br />
The phenomenon of prion strains (disease subtypes with specific clinical, biochemical and neuropathological features, replicating with high fidelity) was initially difficult to equate with the "protein only" hypothesis of prion diseases. However, there is now evidence from a range if studies suggesting that strains are enciphered in the structure of PrP<sup>Sc</sup>. One potential mechanism for this is alternate threading of the β-helix.<br />
<br />
==Selected PrP structures==<br />
All structures determined by NMR spectroscopy unless otherwise specified<br />
===Human PrP===<br />
* [[1qlx]] Residues 23-230 <br />
* [[1qm0]] Residues 90-230 <br />
* [[1qm2]] Residues 121-230 <br />
* [[1i4m]] Determined by X-ray crystallography<br />
* [[1fkc]] E200K mutant (genetic prion disease) <br />
<br />
===PrP from other species===<br />
* [[1xyx]] Mouse PrP <br />
* [[1b10]] Syrian hamster PrP<br />
* [[1dwy]] Cow PrP<br />
* [[1uw3]] Sheep PrP (determined by X-ray crystallography)<br />
* [[1xu0]] Frog PrP<br />
* [[1u3m]] Chicken PrP<br />
* [[1u5l]] Turtle PrP<br />
<br />
==References== <br />
<references/></div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=810869Prion protein2008-12-21T02:24:32Z<p>Kurt Giles: Spacefill disulfide</p>
<hr />
<div>The [[prion protein]] (PrP) is a cell surface glycoprotein, which can exist in two alternatively folded conformations: a cellular isoform denoted (PrP<sup>C</sup>) and a disease associated isoform termed PrP<sup>Sc</sup>. <br />
<br />
==Prion diseases==<br />
The naturally ocuring prion diseases include Creutzfeldt Jakob disease (CJD) in people, bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, scrapie in sheep and goats, and chronic wasting disease in [http://www.wikipedia.org/wiki/Cervidae cervids]. In all cases ''post mortem'' analysis of brain tissue is characterized by aggregates of PrP<sup>Sc</sup>.<br />
The sporadic, genetic and infectious etiologies of prion diseases can be explained by a simple protein-based model in which PrP<sup>C</sup> is converted into PrP<sup>Sc</sup> that in turn initiates an autocatalytic refolding cascade of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
In sporadic prion disease, the spontaneous refolding or misfolding of PrP<sup>C</sup> into PrP<sup>Sc</sup> initiates the cascade. In genetic prion diseases, point mutations in PrP make this structural transition more likely to occur than in the ''wild type'' protein. Infectious etiology is explained by introduction of exogenous PrP<sup>Sc</sup> which then initiates refolding of endogenous PrP<sup>C</sup>.<br />
<br />
==Structure of PrP<sup>C</sup>==<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE=Prion_protein/Cartoon/1 }}<br />
PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230, containing three α-helices and two short β-strands. A <scene name='Prion_protein/1hjm_disulfide_bond/2'>single disulfide bond</scene> connects the middle of helices 2 and 3. The presence of the N-terminal region has little impact on the structure of the C-terminal domain <ref>Zahn, R ''et al.'' (2000) NMR solution structure of the human prion protein ''Proc. Natl. Acad. Sci. USA'' '''97''', 145-150</ref>. The structure of PrP<sup>C</sup> is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians<ref>Calzolai, L ''et al.'' (2005) Prion protein NMR structures of chicken, turtle, and frog ''Proc. Natl. Acad. Sci. USA'' '''102''', 651-655</ref>.<br />
The vast majority of structures have been determined by NMR spectroscopy, but two structures have been reported by X-ray crystallography. In sheep PrP, the X-ray structure is similar to those determined by NMR spectroscopy, however in human PrP, the X-ray structure is a dimer in which helix 3 is swapped between monomers, and the disulphide bond is rearranged to be intermolecular between the dimer subunits.<br />
<br />
==Models of PrP<sup>Sc</sup> structure==<br />
Fourier transform infrared (FTIR) spectroscopy, and circular dichroism (CD) studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><ref>Pan, KM ''et al.'' (1993) Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins ''Proc. Natl. Acad. Sci. USA'' '''90''', 10962-10966</ref>. There are a number of technical obstacles in determining the atomic resolution structure of PrP<sup>Sc</sup>, and the most detailed information to date has been obtained by electron microscopy of 2D crystals<ref>Wille H ''et al.'' (2002) Structural studies of the scrapie prion protein by electron crystallography ''Proc. Natl. Acad. Sci. USA'' '''99''', 3563-3568</ref>. Analysis of 2D crystals binding specific heavy metal ions, and of redacted constructs of PrP, provide a basis for structural modeling.<br />
A model the N-terminal region and part of the C-terminal domain, up to the disulphide bond, refolds into a β-helical structure<ref>Govaerts C ''et al.'' (2004) Ecidence for assembly of prions with left-handed β-helices into trimers ''Proc. Natl. Acad. Sci. USA'' '''101''', 8342-8347</ref>. Support for this β-helical model comes from the structure of the fungal prion Het-s ([[2rnm]]).<br />
<br />
==Prion strains==<br />
The phenomenon of prion strains (disease subtypes with specific clinical, biochemical and neuropathological features, replicating with high fidelity) was initially difficult to equate with the "protein only" hypothesis of prion diseases. However, there is now evidence from a range if studies suggesting that strains are enciphered in the structure of PrP<sup>Sc</sup>. One potential mechanism for this is alternate threading of the β-helix.<br />
<br />
==Selected PrP structures==<br />
All structures determined by NMR spectroscopy unless otherwise specified<br />
===Human PrP===<br />
* [[1qlx]] Residues 23-230 <br />
* [[1qm0]] Residues 90-230 <br />
* [[1qm2]] Residues 121-230 <br />
* [[1i4m]] Determined by X-ray crystallography<br />
* [[1fkc]] E200K mutant (genetic prion disease) <br />
<br />
===PrP from other species===<br />
* [[1xyx]] Mouse PrP <br />
* [[1b10]] Syrian hamster PrP<br />
* [[1dwy]] Cow PrP<br />
* [[1uw3]] Sheep PrP (determined by X-ray crystallography)<br />
* [[1xu0]] Frog PrP<br />
* [[1u3m]] Chicken PrP<br />
* [[1u5l]] Turtle PrP<br />
<br />
==References== <br />
<references/></div>Kurt Gileshttps://proteopedia.org/index.php?title=Doppel&diff=809242Doppel2008-12-15T09:21:36Z<p>Kurt Giles: </p>
<hr />
<div>Doppel (Dpl), named for '''''do'''wnstream '''p'''rion '''p'''rotein-like''<ref>Moore, R ''et al.'' (1999) Ataxia in Prion Protein (PrP)-deficient mice is associated with upregulation of the novel PrP-like protein Doppel ''J. Mol. Biol.'' '''292''', 797-817</ref>, is a homolog of the [[prion protein]] (PrP). It is a cell surface glycoprotein.<br />
<br />
==Structure of Dpl==<br />
<br />
{{STRUCTURE_1lg4 | PDB=1lg4 | SCENE= }}<br />
Dpl has the same fold as PrP, with three alpha helices and two short beta strands<ref>Mo H ''et al.'' (2001) ''Proc. Natl. Acad. Sci. USA'' '''98''',2352-7</ref>. however it differs in that the third helix has a significant kink in it and it also contains two disulphide bonds.<br />
<br />
The structure mutant PrP with the additional disulphide bond was also determoned <ref>Zahn R ''et al.'' (2003) NMR structure of a variant human prion protein with two disulfide bridges '' J. Mol. Biol.'' '''326''', 225-34.</ref><br />
<br />
<br />
==Related structures==<br />
* [[1z65]] Mouse Dpl residues 1-30<br />
* [[1lg4]] Human Dpl residues 24-152<br />
* [[1i17]] Mouse Dpl residues 51-157<br />
* [[1h0l]] Human PrP residues 121-230, with an additional disulphide bond analogous to the homolog [[Doppel]]<br />
<br />
<br />
==References==<br />
<references/></div>Kurt Gileshttps://proteopedia.org/index.php?title=Doppel&diff=809241Doppel2008-12-15T09:21:18Z<p>Kurt Giles: </p>
<hr />
<div>Doppel (Dpl), named for '''''do'''wnstream '''p'''rion '''p'''rotein-like''<ref>Moore, R ''et al.'' (1999) Ataxia in Prion Protein (PrP)-deficient mice is associated with upregulation of the novel PrP-like protein Doppel ''J. Mol. Biol.'' '''292''', 797-817</ref>, is a homolog of the [[prion protein]] (PrP). It is a cell surface glycoprotein.<br />
<br />
==Structure of Dpl==<br />
<br />
{{STRUCTURE_1lg4 | PDB=1lg4 | SCENE= }}<br />
Dpl has the same fold as PrP, with three alpha helices and two short beta strands<ref>Mo H ''et al.'' (2001) ''Proc. Natl. Acad. Sci. USA'' '''98''',2352-7</ref>. however it differs in that the third helix has a significant kink in it and it also contains two disulphide bonds.<br />
<br />
The structure mutant PrP with the additional disulphide bond was also determoned <ref>Zahn R ''et al.'' (2003) NMR structure of a variant human prion protein with two disulfide bridges '' J. Mol. Biol.'' '''326''', 225-34.</ref><br />
<br />
<br />
==Related structures==<br />
* [[1z65]] Mouse Dpl residues 1-30<br />
* [[1lg4]] Human Dpl residues 24-152<br />
* [[1i17]] Mouse Dpl residues 51-157<br />
* [[1h0l]] Human PrP residues 121-230, with an additional disulphide bond analogous to the homolog [[Doppel]]<br />
<br />
<br />
==References==<br />
<reference/></div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=809240Prion protein2008-12-15T09:20:51Z<p>Kurt Giles: </p>
<hr />
<div>The prion protein (PrP) is a cell surface glycoprotein, which can exist in two alternatively folded conformations: a cellular isoform denoted (PrP<sup>C</sup>) and a disease associated isoform termed PrP<sup>Sc</sup>. <br />
<br />
==Prion diseases==<br />
The naturally ocuring prion diseases include Creutzfeldt Jakob disease (CJD) in people, bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, scrapie in sheep and goats, and chronic wasting disease in cervids. In all cases ''post mortem'' analysis of brain tissue is characterized by aggregates of PrP<sup>Sc</sup>.<br />
The sporadic, genetic and infectious etiologies of prion diseases can be explained by a simple protein-based model in which PrP<sup>C</sup> is converted into PrP<sup>Sc</sup> that in turn initiates an autocatalytic refolding cascade of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
In sporadic prion disease, the spontaneous refolding or misfolding of PrP<sup>C</sup> into PrP<sup>Sc</sup> initiates the cascade. In genetic prion diseases, point mutations in PrP make this structural transition more likely to occur than in the ''wild type'' protein. Infectious etiology is explained by introduction of exogenous PrP<sup>Sc</sup> which then initiates refolding of endogenous PrP<sup>C</sup>.<br />
<br />
==Structure of PrP<sup>C</sup>==<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE=Prion_protein/Cartoon/1 }}<br />
PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230, containing three α-helices and two short β-strands. A single disulfide bond connects the middle of helices 2 and 3. The presence of the N-terminal region has little impact on the structure of the C-terminal domain <ref>Zahn, R ''et al.'' (2000) NMR solution structure of the human prion protein ''Proc. Natl. Acad. Sci. USA'' '''97''', 145-150</ref>. The structure of PrP<sup>C</sup> is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians<ref>Calzolai, L ''et al.'' (2005) Prion protein NMR structures of chicken, turtle, and frog ''Proc. Natl. Acad. Sci. USA'' '''102''', 651-655</ref>.<br />
The vast majority of structures have been determined by NMR spectroscopy, but two structures have been reported by X-ray crystallography. In sheep PrP, the X-ray structure is similar to those determined by NMR spectroscopy, however in human PrP, the X-ray structure is a dimer in which helix 3 is swapped between monomers, and the disulphide bond is rearranged to be intermolecular between the dimer subunits.<br />
<br />
==Models of PrP<sup>Sc</sup> structure==<br />
Fourier transform infrared (FTIR) spectroscopy, and circular dichroism (CD) studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><ref>Pan, KM ''et al.'' (1993) Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins ''Proc. Natl. Acad. Sci. USA'' '''90''', 10962-10966</ref>. There are a number of technical obstacles in determining the atomic resolution structure of PrP(sup)Sc</sup>, and the most detailed information to date has been obtained by electron microscopy of 2D crystals<ref>Wille H ''et al.'' (2002) Structural studies of the scrapie prion protein by electron crystallography ''Proc. Natl. Acad. Sci. USA'' '''99''', 3563-3568</ref>. Analysis of 2D crystals binding specific heavy metal ions, and of redacted constructs of PrP, provide a basis for structural modeling.<br />
A model the N-terminal region and part of the C-terminal domain, up to the disulphide bond, refolds into a β-helical structure<ref>Govaerts C ''et al.'' (2004) Ecidence for assembly of prions with left-handed β-helices into trimers ''Proc. Natl. Acad. Sci. USA'' '''101''', 8342-8347</ref>. Support for this β-helical model comes from the structure of the fungal prion Het-s ([[2rnm]]).<br />
<br />
==Prion strains==<br />
The phenomenon of prion strains (disease subtypes with specific clinical, biochemical and neuropathological features, replicating with high fidelity) was initially difficult to equate with the "protein only" hypothesis of prion diseases. However, there is now evidence from a range if studies suggesting that strains are enciphered in the structure of PrP<sup>Sc</sup>. One potential mechanism for this is alternate threading of the β-helix.<br />
<br />
==Selected PrP structures==<br />
All structures determined by NMR spectroscopy unless otherwise specified<br />
===Human PrP===<br />
* [[1qlx]] Residues 23-230 <br />
* [[1qm0]] Residues 90-230 <br />
* [[1qm2]] Residues 121-230 <br />
* [[1i4m]] Determined by X-ray crystallography<br />
* [[1fkc]] E200K mutant (genetic prion disease) <br />
<br />
===PrP from other species===<br />
* [[1xyx]] Mouse PrP <br />
* [[1b10]] Syrian hamster PrP<br />
* [[1dwy]] Cow PrP<br />
* [[1uw3]] Sheep PrP (determined by X-ray crystallography)<br />
* [[1xu0]] Frog PrP<br />
* [[1u3m]] Chicken PrP<br />
* [[1u5l]] Turtle PrP<br />
<br />
==References== <br />
<references/></div>Kurt Gileshttps://proteopedia.org/index.php?title=Doppel&diff=809239Doppel2008-12-15T09:20:03Z<p>Kurt Giles: </p>
<hr />
<div>Doppel (Dpl), named for '''''do'''wnstream '''p'''rion '''p'''rotein-like''<ref>Moore, R ''et al.'' (1999) Ataxia in Prion Protein (PrP)-deficient mice is associated with upregulation of the novel PrP-like protein Doppel ''J. Mol. Biol.'' '''292''', 797-817</ref>, is a homolog of the [[prion protein]] (PrP). It is a cell surface glycoprotein.<br />
<br />
==Structure of Dpl==<br />
<br />
{{STRUCTURE_1lg4 | PDB=1lg4 | SCENE= }}<br />
Dpl has the same fold as PrP, with three alpha helices and two short beta strands<ref>Mo H ''et al.'' (2001) ''Proc. Natl. Acad. Sci. USA'' '''98''',2352-7</ref>. however it differs in that the third helix has a significant kink in it and it also contains two disulphide bonds.<br />
<br />
The structure mutant PrP with the additional disulphide bond was also determoned <ref>Zahn R ''et al.'' (2003) NMR structure of a variant human prion protein with two disulfide bridges '' J. Mol. Biol.'' '''326''', 225-34.</ref><br />
<br />
<br />
==Related structures==<br />
* [[1z65]] Mouse Dpl residues 1-30<br />
* [[1lg4]] Human Dpl residues 24-152<br />
* [[1i17]] Mouse Dpl residues 51-157<br />
* [[1h0l]] Human PrP residues 121-230, with an additional disulphide bond analogous to the homolog [[Doppel]]<br />
<br />
<br />
==References==<br />
</reference></div>Kurt Gileshttps://proteopedia.org/index.php?title=Doppel&diff=809238Doppel2008-12-15T09:18:50Z<p>Kurt Giles: </p>
<hr />
<div>Doppel (Dpl), named for '''''do'''wnstream '''p'''rion '''p'''rotein-like''<ref>Moore, R ''et al.'' (1999) Ataxia in Prion Protein (PrP)-deficient mice is associated with upregulation of the novel PrP-like protein Doppel ''J. Mol. Biol.'' '''292''', 797-817</ref>, is a homolog of the [[prion protein]] (PrP). It is a cell surface glycoprotein.<br />
<br />
==Structure of Dpl==<br />
<br />
{{STRUCTURE_1lg4 | PDB=1lg4 | SCENE= }}<br />
Dpl has the same fold as PrP, with three alpha helices and two short beta strands<ref>Mo H ''et al.'' (2001) ''Proc. Natl. Acad. Sci. USA'' '''98''',2352-7</ref>. however it differs in that the third helix has a significant kink in it and it also contains two disulphide bonds.<br />
<br />
The structure mutant PrP with the additional disulphide bond was also determoned <ref>Zahn R ''et al.'' (2003) NMR structure of a variant human prion protein with two disulfide bridges '' J. Mol. Biol.'' '''326''', 225-34.<br />
<br />
<br />
=Related structures=<br />
* [[1z65]] Mouse Dpl residues 1-30<br />
* [[1lg4]] Human Dpl residues 24-152<br />
* [[1i17]] Mouse Dpl residues 51-157<br />
* [[1h0l]] Human PrP residues 121-230, with an additional disulphide bond analogous to the homolog [[Doppel]]<br />
<br />
<br />
=References=<br />
</reference></div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=809237Prion protein2008-12-15T09:03:57Z<p>Kurt Giles: </p>
<hr />
<div>The prion protein (PrP) is a cell surface glycoprotein, which can exist in two alternatively folded conformations: a cellular isoform denoted (PrP<sup>C</sup>) and a disease associated isoform termed PrP<sup>Sc</sup>. <br />
<br />
==Prion diseases==<br />
The naturally ocuring prion diseases include Creutzfeldt Jakob disease (CJD) in people, bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, scrapie in sheep and goats, and chronic wasting disease in cervids. In all cases ''post mortem'' analysis of brain tissue is characterized by aggregates of PrP<sup>Sc</sup>.<br />
The sporadic, genetic and infectious etiologies of prion diseases can be explained by a simple protein-based model in which PrP<sup>C</sup> is converted into PrP<sup>Sc</sup> that in turn initiates an autocatalytic refolding cascade of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
In sporadic prion disease, the spontaneous refolding or misfolding of PrP<sup>C</sup> into PrP<sup>Sc</sup> initiates the cascade. In genetic prion diseases, point mutations in PrP make this structural transition more likely to occur than in the ''wild type'' protein. Infectious etiology is explained by introduction of exogenous PrP<sup>Sc</sup> which then initiates refolding of endogenous PrP<sup>C</sup>.<br />
<br />
==Structure of PrP<sup>C</sup>==<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE=Prion_protein/Cartoon/1 }}<br />
PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230, containing three α-helices and two short β-strands. A single disulfide bond connects the middle of helices 2 and 3. The presence of the N-terminal region has little impact on the structure of the C-terminal domain <ref>Zahn, R ''et al.'' (2000) NMR solution structure of the human prion protein ''Proc. Natl. Acad. Sci. USA'' '''97''', 145-150</ref>. The structure of PrP<sup>C</sup> is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians<ref>Calzolai, L ''et al.'' (2005) Prion protein NMR structures of chicken, turtle, and frog ''Proc. Natl. Acad. Sci. USA'' '''102''', 651-655</ref>.<br />
The vast majority of structures have been determined by NMR spectroscopy, but two structures have been reported by X-ray crystallography. In sheep PrP, the X-ray structure is similar to those determined by NMR spectroscopy, however in human PrP, the X-ray structure is a dimer in which helix 3 is swapped between monomers, and the disulphide bond is rearranged to be intermolecular between the dimer subunits.<br />
<br />
==Models of PrP<sup>Sc</sup> structure==<br />
Fourier transform infrared (FTIR) spectroscopy, and circular dichroism (CD) studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><ref>Pan, KM ''et al.'' (1993) Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins ''Proc. Natl. Acad. Sci. USA'' '''90''', 10962-10966</ref>. There are a number of technical obstacles in determining the atomic resolution structure of PrP(sup)Sc</sup>, and the most detailed information to date has been obtained by electron microscopy of 2D crystals<ref>Wille H ''et al.'' (2002) Structural studies of the scrapie prion protein by electron crystallography ''Proc. Natl. Acad. Sci. USA'' '''99''', 3563-3568</ref>. Analysis of 2D crystals binding specific heavy metal ions, and of redacted constructs of PrP, provide a basis for structural modeling.<br />
A model the N-terminal region and part of the C-terminal domain, up to the disulphide bond, refolds into a β-helical structure<ref>Govaerts C ''et al.'' (2004) Ecidence for assembly of prions with left-handed β-helices into trimers ''Proc. Natl. Acad. Sci. USA'' '''101''', 8342-8347</ref>. Support for this β-helical model comes from the structure of the fungal prion Het-s ([[2rnm]]).<br />
<br />
==Prion strains==<br />
The phenomenon of prion strains (disease subtypes with specific clinical, biochemical and neuropathological features, replicating with high fidelity) was initially difficult to equate with the "protein only" hypothesis of prion diseases. However, there is now evidence from a range if studies suggesting that strains are enciphered in the structure of PrP<sup>Sc</sup>. One potential mechanism for this is alternate threading of the β-helix.<br />
<br />
==Selected PrP structures==<br />
All structures determined by NMR spectroscopy unless otherwise specified<br />
===Human PrP===<br />
* [[1qlx]] Residues 23-230 <br />
* [[1qm0]] Residues 90-230 <br />
* [[1qm2]] Residues 121-230 <br />
* [[1i4m]] Determined by X-ray crystallography<br />
* [[1fkc]] E200K mutant (genetic prion disease) <br />
<br />
===PrP from other species===<br />
* [[1xyx]] Mouse PrP <br />
* [[1b10]] Syrian hamster PrP<br />
* [[1dwy]] Cow PrP<br />
* [[1uw3]] Sheep PrP (determined by X-ray crystallography)<br />
* [[1xu0]] Frog PrP<br />
* [[1u3m]] Chicken PrP<br />
* [[1u5l]] Turtle PrP<br />
<br />
=References= <br />
<references/></div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=809236Prion protein2008-12-15T09:01:53Z<p>Kurt Giles: </p>
<hr />
<div>The prion protein (PrP) is a cell surface glycoprotein, which can exist in two alternatively folded conformations: a cellular isoform denoted (PrP<sup>C</sup>) and a disease associated isoform termed PrP<sup>Sc</sup>. <br />
<br />
==Prion diseases==<br />
The naturally ocuring prion diseases include Creutzfeldt Jakob disease (CJD) in people, bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, scrapie in sheep and goats, and chronic wasting disease in cervids. In all cases ''post mortem'' analysis of brain tissue is characterized by aggregates of PrP<sup>Sc</sup>.<br />
The sporadic, genetic and infectious etiologies of prion diseases can be explained by a simple protein-based model in which PrP<sup>C</sup> is converted into PrP<sup>Sc</sup> that in turn initiates an autocatalytic refolding cascade of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
In sporadic prion disease, the spontaneous refolding or misfolding of PrP<sup>C</sup> into PrP<sup>Sc</sup> initiates the cascade. In genetic prion diseases, point mutations in PrP make this structural transition more likely to occur than in the ''wild type'' protein. Infectious etiology is explained by introduction of exogenous PrP<sup>Sc</sup> which then initiates refolding of endogenous PrP<sup>C</sup>.<br />
<br />
==Structure of PrP<sup>C</sup>==<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE=Prion_protein/Cartoon/1 }}<br />
PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230, containing three α-helices and two short β-strands. A single disulfide bond connects the middle of helices 2 and 3. The presence of the N-terminal region has little impact on the structure of the C-terminal domain <ref>Zahn, R ''et al.'' (2000) NMR solution structure of the human prion protein ''Proc. Natl. Acad. Sci. USA'' '''97''', 145-150</ref>. The structure of PrP<sup>C</sup> is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians<ref>Calzolai, L ''et al.'' (2005) Prion protein NMR structures of chicken, turtle, and frog ''Proc. Natl. Acad. Sci. USA'' '''102''', 651-655</ref>.<br />
The vast majority of structures have been determined by NMR spectroscopy, but two structures have been reported by X-ray crystallography. In sheep PrP, the X-ray structure is similar to those determined by NMR spectroscopy, however in human PrP, the X-ray structure is a dimer in which helix 3 is swapped between monomers, and the disulphide bond is rearranged to be intermolecular between the dimer subunits.<br />
<br />
==Models of PrP<sup>Sc</sup> structure==<br />
Fourier transform infrared (FTIR) spectroscopy, and circular dichroism (CD) studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><ref>Pan, KM ''et al.'' (1993) Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins ''Proc. Natl. Acad. Sci. USA'' '''90''', 10962-10966</ref>. There are a number of technical obstacles in determining the atomic resolution structure of PrP(sup)Sc</sup>, and the most detailed information to date has been obtained by electron microscopy of 2D crystals<ref>Wille H ''et al.'' (2002) Structural studies of the scrapie prion protein by electron crystallography ''Proc. Natl. Acad. Sci. USA'' '''99''', 3563-3568</ref>. Analysis of 2D crystals binding specific heavy metal ions, and of redacted constructs of PrP, provide a basis for structural modeling.<br />
A model the N-terminal region and part of the C-terminal domain, up to the disulphide bond, refolds into a β-helical structure<ref>Govaerts C ''et al.'' (2004) Ecidence for assembly of prions with left-handed β-helices into trimers ''Proc. Natl. Acad. Sci. USA'' '''101''', 8342-8347<ref>. Support for this β-helical model comes from the structure of the fungal prion Het-s ([[2rnm]]).<br />
<br />
==Prion strains==<br />
The phenomenon of prion strains (disease subtypes with specific clinical, biochemical and neuropathological features, replicating with high fidelity) was initially difficult to equate with the "protein only" hypothesis of prion diseases. However, there is now evidence from a range if studies suggesting that strains are enciphered in the structure of PrP<sup>Sc</sup>. One potential mechanism for this is alternate threading of the β-helix.<br />
<br />
==Selected PrP structures==<br />
All structures determined by NMR spectroscopy unless otherwise specified<br />
===Human PrP===<br />
* [[1qlx]] Residues 23-230 <br />
* [[1qm0]] Residues 90-230 <br />
* [[1qm2]] Residues 121-230 <br />
* [[1i4m]] Determined by X-ray crystallography<br />
* [[1fkc]] E200K mutant (genetic prion disease) <br />
<br />
===PrP from other species===<br />
* [[1xyx]] Mouse PrP <br />
* [[1b10]] Syrian hamster PrP<br />
* [[1dwy]] Cow PrP<br />
* [[1uw3]] Sheep PrP (determined by X-ray crystallography)<br />
* [[1xu0]] Frog PrP<br />
* [[1u3m]] Chicken PrP<br />
* [[1u5l]] Turtle PrP<br />
<br />
=References= <br />
<references/></div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=809235Prion protein2008-12-15T08:58:17Z<p>Kurt Giles: </p>
<hr />
<div>The prion protein (PrP) is a cell surface glycoprotein, which can exist in two alternatively folded conformations: a cellular isoform denoted (PrP<sup>C</sup>) and a disease associated isoform termed PrP<sup>Sc</sup>. <br />
<br />
==Prion diseases==<br />
The naturally ocuring prion diseases include Creutzfeldt Jakob disease (CJD) in people, bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, scrapie in sheep and goats, and chronic wasting disease in cervids. In all cases ''post mortem'' analysis of brain tissue is characterized by aggregates of PrP<sup>Sc</sup>.<br />
The sporadic, genetic and infectious etiologies of prion diseases can be explained by a simple protein-based model in which PrP<sup>C</sup> is converted into PrP<sup>Sc</sup> that in turn initiates an autocatalytic refolding cascade of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
In sporadic prion disease, the spontaneous refolding or misfolding of PrP<sup>C</sup> into PrP<sup>Sc</sup> initiates the cascade. In genetic prion diseases, point mutations in PrP make this structural transition more likely to occur than in the ''wild type'' protein. Infectious etiology is explained by introduction of exogenous PrP<sup>Sc</sup> which then initiates refolding of endogenous PrP<sup>C</sup>.<br />
<br />
==Structure of PrP<sup>C</sup>==<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE=Prion_protein/Cartoon/1 }}<br />
PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230, containing three α-helices and two short β-strands. A single disulfide bond connects the middle of helices 2 and 3. The presence of the N-terminal region has little impact on the structure of the C-terminal domain <ref>Zahn, R ''et al.'' (2000) NMR solution structure of the human prion protein ''Proc. Natl. Acad. Sci. USA'' '''97''', 145-150</ref>. The structure of PrP<sup>C</sup> is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians<ref>Calzolai, L ''et al.'' (2005) Prion protein NMR structures of chicken, turtle, and frog ''Proc. Natl. Acad. Sci. USA'' '''102''', 651-655</ref>.<br />
The vast majority of structures have been determined by NMR spectroscopy, but two structures have been reported by X-ray crystallography. In sheep PrP, the X-ray structure is similar to those determined by NMR spectroscopy, however in human PrP, the X-ray structure is a dimer in which helix 3 is swapped between monomers, and the disulphide bond is rearranged to be intermolecular between the dimer subunits.<br />
<br />
==Models of PrP<sup>Sc</sup> structure==<br />
Fourier transform infrared (FTIR) spectroscopy, and circular dichroism (CD) studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><ref>Pan, KM ''et al.'' (1993) Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins ''Proc. Natl. Acad. Sci. USA'' '''90''', 10962-10966</ref>. There are a number of technical obstacles in determining the atomic resolution structure of PrP(sup)Sc</sup>, and the most detailed information to date has been obtained by electron microscopy of 2D crystals<ref>Wille H ''et al.'' (2002) Structural studies of the scrapie prion protein by electron crystallography ''Proc. Natl. Acad. Sci. USA'' '''99''', 3563-3568</ref>. Analysis of 2D crystals binding specific heavy metal ions, and of redacted constructs of PrP, provide a basis for structural modeling.<br />
A model the N-terminal region and part of the C-terminal domain, up to the disulphide bond, refolds into a β-helical structure<ref>Govaerts C ''et al.'' (2004) Ecidence for assembly of prions with left-handed β-helices into trimers ''Proc. Natl. Acad. Sci. USA'' '''101''', 8342-8347<ref>. Support for this β-helical model comes from the structure of the fungal prion Het-s ([[2rnm]]).<br />
<br />
==Prion strains==<br />
The phenomenon of prion strains (disease subtypes with specific clinical, biochemical and neuropathological features, replicating with high fidelity) was initially difficult to equate with the "protein only" hypothesis of prion diseases. However, there is now evidence from a range if studies suggesting that strains are enciphered in the structure of PrP<sup>Sc</sup>. One potential mechanism for this is alternate threading of the β-helix.<br />
<br />
==Selected PrP structures==<br />
All structures determined by NMR spectroscopy unless otherwise specified<br />
===Human PrP===<br />
* [[1qlx]] Residues 23-230 <br />
* [[1qm0]] Residues 90-230 <br />
* [[1qm2]] Residues 121-230 <br />
* [[1i4m]] Residues 119-226 (determined by X-ray crystallography) <br />
* [[1fkc]] E200K mutant (genetic prion disease), residues 90-231 <br />
<br />
===PrP from other species===<br />
* [[1xyx]] Mouse PrP residues <br />
* [[1b10]] Syrian hamster PrP residues 90-231<br />
* [[1dwy]] Cow PrP residues 121-230<br />
* [[1uw3]] Sheep PrP (determined by X-ray crystallography)<br />
* [[1xu0]] Frog PrP residues 98-226<br />
* [[1u3m]] Chicken PrP<br />
* [[1u5l]] Turtle PrP residues 121-226<br />
<br />
=References= <br />
<references/></div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=809220Prion protein2008-12-14T16:08:59Z<p>Kurt Giles: </p>
<hr />
<div>The prion protein (PrP) is a cell surface glycoprotein, which can exist in two alternatively folded conformations: a cellular isoform denoted (PrP<sup>C</sup>) and a disease associated isoform termed PrP<sup>Sc</sup>. <br />
<br />
=Prion diseases=<br />
The naturally ocuring prion diseases include Creutzfeldt Jakob disease (CJD) in people, bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, scrapie in sheep and goats, and chronic wasting disease in cervids. In all cases ''post mortem'' analysis of brain tissue is characterterized by aggregates of PrP<sup>Sc</sup>.<br />
The sporadic, genetic and infectious etiologies of prion diseases can be explained by a simple protein-based model in which PrP<sup>C</sup> is converted into PrP<sup>Sc</sup> which in turn initiates an autocatalytic refolding cascade of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
In sporadic prion disease, the spontaneous refolding or misfolding of PrP<sup>C</sup> into PrP<sup>Sc</sup> initiates the cascade. In genetic prion diseases, point mutations in PrP make this structural transition more likely to happen than in the wild type protein, Infectious etiology is explained by introduction of exogenous PrP<sup>Sc</sup> which then initiates refolding of endogenous PrP<sup>C</sup>.<br />
<br />
=Structure of PrP<sup>C</sup>=<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE=Prion_protein/Cartoon/1 }}<br />
PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230. containing three α-helices and two short β-strands. A single disulfide bond connects the middle of helices 2 and 3. The presence of the N-terminal region has little impact on the structure of the C-terminal domain <ref>Zahn, R. ''et al.'' (2000) NMR solution structure of the human prion protein ''Proc. Natl. Acad. Sci. USA'' '''97''', 145-150 </ref>. The structure of PrP<sup>C</sup> is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians<ref>Calzolai, L ''et al.'' (2005) Prion protein NMR structures of chicken, turtle, and frog 'Proc. Natl. Acad. Sci. USA'' '''102''', 651-655</ref>.<br />
The vast majority of structures have been determined by NMR spectroscopy, but two structures have been reported by X-ray crystallography. In sheep PrP, the X-ray structure is similar to other PrPs determined by NMR spectroscopy, however in human PrP, the X-ray structure is a dimer in which helix 3 is swapped with respect to the monomer, and the disulphide bond is rearranged to be intermolecular between the dimer subunits.<br />
<br />
=Models of PrP<sup>Sc</sup> structure=<br />
Fourier transform infrared (FTIR) spectroscopy, and circular dichroism (CD) studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><ref>Pan, KM ''et al.'' (1993) Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins ''Proc. Natl. Acad. Sci. USA'' '''90''', 10962-10966</ref>. There are a number of technical obstacles in determining the atomic resolution structure of PrP(sup)Sc</sup>, and the most detailed information to date has been obtained by electron microscopy of 2D crystals. Differential binding of metal ions to these 2D crystals, and redacted constructs of PrP, provide a basis for structural modeling.<br />
A model the N-terminal region and much of the C-terminal domain, up to the disulphide bond, refolds into a β-helical structure<br />
Support for this β-helical model comes from the structure of the fungal prion Het-s ([[2rnm]]).<br />
<br />
=Prion strains=<br />
The strain phenomenon of prion strains (disease subtype replicating with high fidelity and producing specific clinical, biochemical and neuropathological features) was initially difficult to equate with the "protein only" hypothesis of prion diseases. However, there is now evidence from a range if studies suggesting that strains are enciphered in the structure of PrP<sup>Sc</sup>. One potential mechanism for this is alternate threading of the β-helix.<br />
<br />
=Selected PrP structures=<br />
All structures determined by NMR unless otherwise specified<br />
==Human PrP==<br />
* [[1qlx]] HuPrP residues 23-230 <br />
* [[1qm0]] HuPrP residues 90-230 <br />
* [[1qm2]] HuPrP residues 121-230 <br />
* [[1i4m]] HuPrP residues 119-226 (determined by X-ray crystallography) <br />
* [[1fkc]] HuPrP,E200K residues 90-231 (genetic prion disease)<br />
* [[1h0l]] HuPrP residues 121-230, with an additional disulphide bond analogous to the homolog [[Doppel]]<br />
<br />
==Other species PrPs==<br />
* [[1xyx]] Mouse PrP residues <br />
* [[1b10]] Syrian hamster PrP residues 90-231<br />
* [[1dwy]] Cow PrP residues 121-230<br />
* [[1uw3]] Sheep PrP (determined by X-ray crystallography)<br />
* [[1xu0]] Frog PrP residues 98-226<br />
* [[1u3m]] Chicken PrP<br />
* [[1u5l]] Turtle PrP residues 121-226<br />
<br />
=References= <br />
<references/></div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=809219Prion protein2008-12-14T15:59:40Z<p>Kurt Giles: </p>
<hr />
<div>The prion protein (PrP) is a cell surface glycoprotein, which can exist in two alternatively folded conformations: a cellular isoform denoted (PrP<sup>C</sup>) and a disease associated isoform termed PrP<sup>Sc</sup>. <br />
<br />
=Prion diseases=<br />
The naturally ocuring prion diseases include Creutzfeldt Jakob disease (CJD) in people, bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, scrapie in sheep and goats, and chronic wasting disease in cervids. ''Post mortem'' analysis of brain tissue is characterterized by aggregates of PrP<sup>Sc</sup>.<br />
The spontaneous, genetic and infectious etiologies of prion diseases can be explained by a simple protein-based model in which PrP<sup>C</sup> is converted into PrP<sup>Sc</sup> that initiates a cascade of autocatalytic refolding of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
In sporadic disease, the spontaneous refolding or misfolding of PrP<sup>C</sup> into PrP<sup>Sc</sup> initiates the cascade. In genetic prion diseases, point mutations in PrP make this structural transition more likely to happen than in the wild type protein, Infectious etiology is explained by introduction of exogenous PrP<sup>Sc</sup> which then initiates refolding of endogenous PrP<sup>C</sup>.<br />
<br />
=Structure of PrP<sup>C</sup>=<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE= }}<br />
PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230. containing three α-helices and two short β-strands. A single disulfide bond connects the middle of helices 2 and 3. The presence of the N-terminal region has little impact on the structure of the C-terminal domain <ref>Zahn, R. ''et al.'' (2000) NMR solution structure of the human prion protein ''Proc. Natl. Acad. Sci. USA'' '''97''', 145-150 </ref>.<br />
<br />
, and the structure of PrP<sup>C</sup> is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians<ref>[[Pan, KM ''et al.'' (1993) Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins ''Proc. Natl. Acad. Sci. USA'' '''90''', 10962-10966}}</ref>.<br />
The vast majority of structures have been determined by NMR spectroscopy, but two structures have been reported by X-ray crystallography. In sheep PrP, the structure is similar to other PrPs determined by NMR spectroscopy, however in human PrP, the X-ray structure is a dimer in which helix 3 is swapped with respect to the monomer and the disulphide bond is rearranged to be intermolecular between the dimer subunits.<br />
<br />
<br />
=Models of PrP<sup>Sc</sup> structure=<br />
Fourier transform infrared (FTIR) spectroscopy, and circular dichroism (CD) studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><ref>{{Calzolai, L ''et al.'' (2005) Prion protein NMR structures of chicken, turtle, and frog 'Proc. Natl. Acad. Sci. USA'' '''102''', 651-655}}</ref>.<br />
There are a number of technical obstacles in determining the molecular structure of PrP(sup)Sc</sup>, and the highest resolution structural information to date has been obtained by electron microscopy of 2D crystals. Differential binding of metal ions to these 2D crystals, and redacted constructs of PrP, provide a basis for structural modeling.<br />
A model the N-terminal region and much of the C-terminal domain, up to the disulphide bond, refolds into a β-helical structure<br />
Support for this β-helical model comes from the structure of the fungal prion Het-s ([[2rnm]]).<br />
<br />
=Prion strains=<br />
The strain phenomenon of prion strains (disease subtype replicating with high fidelity and producing specific clinical, biochemical and neuropathological features) was initially difficult to equate with the "protein only" hypothesis of prion diseases. However, there is now evidence from a range if studies suggesting that strains are enciphered in the structure of PrP<sup>Sc</sup>. One potential mechanism for this is alternate threading of the β-helix.<br />
<br />
=Selected PrP structures=<br />
All structures determined by NMR unless otherwise specified<br />
==Human PrP==<br />
* [[1qlx]] HuPrP residues 23-230 <br />
* [[1qm0]] HuPrP residues 90-230 <br />
* [[1qm2]] HuPrP residues 121-230 <br />
* [[1i4m]] HuPrP residues 119-226 (determined by X-ray crystallography) <br />
* [[1fkc]] HuPrP,E200K residues 90-231 (genetic prion disease)<br />
* [[1h0l]] HuPrP residues 121-230, with an additional disulphide bond analogous to the homolog [[Doppel]]<br />
<br />
==Other species PrPs==<br />
* [[1xyx]] Mouse PrP residues <br />
* [[1b10]] Syrian hamster PrP residues 90-231<br />
* [[1dwy]] Cow PrP residues 121-230<br />
* [[1uw3]] Sheep PrP (determined by X-ray crystallography)<br />
* [[1xu0]] Frog PrP residues 98-226<br />
* [[1u3m]] Chicken PrP<br />
* [[1u5l]] Turtle PrP residues 121-226<br />
<br />
=References= <br />
<references/></div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=809210Prion protein2008-12-14T12:58:36Z<p>Kurt Giles: Cartoon</p>
<hr />
<div>The prion protein (PrP) is a cell surface glycoprotein, which can exist in two alternatively folded confirmations: the cellular isoform (PrP<sup>C</sup>) can undergo a structural conversion to a 'scrapie' or disease associated isoform termed PrP<sup>Sc</sup>. <br />
<br />
=Prion diseases=<br />
The naturally ocuring prion diseases include Creutzfeldt Jakob disease (CJD) in people, bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease,scpie in sheep and goats, and chronic wasting disease in cervids.<br />
are characterterized by aggregates of PrP<sup>Sc</sup>.<br />
The spontaneous, genetic and infectious etiologies of prion diseases can be explained by a simple protein-based model in which PrP<sup>C</sup> is converted into PrP<sup>Sc</sup>, which then initiates autocatalytic refolding of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
In sporadic disease, the spontaneous refolding or misfolding of PrP<sup>C</sup> into PrP<sup>Sc</sup> initiates the cascade. In genetic prion diseases, point mutations in PrP make this more likely to happen than in the wild type protein, Infectious etiology is explained by introduction of exogenous PrP<sup>Sc</sup> which then initiated refolding of endogenous PrP<sup>C</sup>.<br />
<br />
=Structure of PrP<sup>C</sup>=<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE= }}<br />
PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230, with a single disulfide bond. The presence of the N-terminal region has little impact on the structure of the C-terminal domain <ref>1</ref>.<br />
<br />
The structure is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians.<br />
The vast majority of structures have been determined by<br />
<br />
Although having a similar overall fold, the X-ray structure of sheep PrP was dimeric <br />
<br />
=Models of PrP<sup>Sc</sup> structure=<br />
Circular dichroism studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><br />
<br />
<br />
<br />
There are a number of technical obstacles in determining the molecular structure of PrP(sup)Sc</sup><br />
<br />
<ref>10</ref><br />
<br />
=Genetic prion diseases=<br />
A number of mutations in PrP have been identified which correlate with a high incidence of prion disease. The structure of HuPrP,E200K was determined nd shown to be To date, structural studies of all mutant PrP<sup>C</sup> have extremely similar structures to wild type PrP<sup>C</sup>, suggesting a kinetic basis for the difference in converting to PrP<sup>Sc</sup>.<br />
<br />
=Prion strains=<br />
The strain phenomenon of prions ( ) was initially difficult to equate with the <br />
<br />
<br />
=Selected PrP structures=<br />
All structures determined by NMR unless otherwise specified<br />
==Human PrP==<br />
* [[1qlx]] HuPrP residues 23-230 <br />
* [[1qm0]] HuPrP residues 90-230 <br />
* [[1qm2]] HuPrP residues 121-230 <br />
* [[1i4m]] HuPrP residues 119-226 (determined by X-ray crystallography) <br />
* [[1fkc]] HuPrP,E200K residues 90-231 (genetic prion disease)<br />
* [[1h0l]] HuPrP residues 121-230, with an additional disulphide bond analogous to the homolog [[Doppel]]<br />
<br />
==Other species PrPs==<br />
* [[1xyx]] Mouse PrP residues <br />
* [[1b10]] Syrian hamster PrP residues 90-231<br />
* [[1dwy]] Cow PrP residues 121-230<br />
* [[1uw3]] Sheep PrP (determined by X-ray crystallography)<br />
* [[1xu0]] Frog PrP residues 98-226<br />
* [[1u3m]] Chicken PrP<br />
* [[1u5l]] Turtle PrP residues 121-226<br />
<br />
=References=<br />
{{Reflist}} <br />
Zahn, R. ''et al.'' (2000) NMR solution structure of the human prion protein ''Proc. Natl. Acad. Sci. USA'' '''97''', 145-150 <br />
<references/></div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=809208Prion protein2008-12-14T12:39:08Z<p>Kurt Giles: </p>
<hr />
<div>The prion protein (PrP) is a cell surface glycoprotein, which can exist in two alternatively folded confirmations: the cellular isoform (PrP<sup>C</sup>) can undergo a structural conversion to a 'scrapie' or disease associated isoform termed PrP<sup>Sc</sup>. Prion diseases such as Creutzfeldt Jakob disease (CJD) in people, and bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, are characterterized by aggregates of PrP<sup>Sc</sup>, which arise from autocatalytic refolding of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
=Structure of PrP<sup>C</sup>=<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE= }}<br />
PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230, with a single disulfide bond. The presence of the N-terminal region has little impact on the structure of the C-terminal domain <ref>1</ref>.<br />
<br />
The structure is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians.<br />
The vast majority of structures have been determined by<br />
<br />
Although having a similar overall fold, the X-ray structure of sheep PrP was dimeric <br />
<br />
=Models of PrP<sup>Sc</sup> structure=<br />
Circular dichroism studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><br />
<br />
There are a number of technical obstacles in determining the molecular structure of PrP(sup)Sc</sup><br />
<br />
<ref>10</ref><br />
<br />
=Genetic prion diseases=<br />
A number of mutations in PrP have been identified which correlate with a high incidence of prion disease. The structure of HuPrP,E200K was determined nd shown to be To date, structural studies of all mutant PrP<sup>C</sup> have extremely similar structures to wild type PrP<sup>C</sup>, suggesting a kinetic basis for the difference in converting to PrP<sup>Sc</sup>.<br />
<br />
=Prion strains=<br />
The strain phenomenon of prions ( ) was initially difficult to equate with the <br />
<br />
<br />
=Selected PrP structures=<br />
All structures determined by NMR unless otherwise specified<br />
==Human PrP==<br />
* [[1qlx]] HuPrP residues 23-230 <br />
* [[1qm0]] HuPrP residues 90-230 <br />
* [[1qm2]] HuPrP residues 121-230 <br />
* [[1i4m]] HuPrP residues 119-226 (determined by X-ray crystallography) <br />
* [[1fkc]] HuPrP,E200K residues 90-231 (genetic prion disease)<br />
* [[1h0l]] HuPrP residues 121-230, with an additional disulphide bond analogous to the homolog [[Doppel]]<br />
<br />
==Other species PrPs==<br />
* [[1xyx]] Mouse PrP residues <br />
* [[1b10]] Syrian hamster PrP residues 90-231<br />
* [[1dwy]] Cow PrP residues 121-230<br />
* [[1uw3]] Sheep PrP (determined by X-ray crystallography)<br />
* [[1xu0]] Frog PrP residues 98-226<br />
* [[1u3m]] Chicken PrP<br />
* [[1u5l]] Turtle PrP residues 121-226<br />
<br />
=References=<br />
{{Reflist}} <br />
Zahn, R. ''et al.'' (2000) NMR solution structure of the human prion protein ''Proc. Natl. Acad. Sci. USA'' '''97''', 145-150 <br />
<references/></div>Kurt Gileshttps://proteopedia.org/index.php?title=Doppel&diff=809207Doppel2008-12-14T12:23:01Z<p>Kurt Giles: </p>
<hr />
<div>Doppel (Dpl), named for '''''do'''wnstream '''p'''rion '''p'''rotein like''<ref>1</ref>, is a homolog of the [[prion protein]] (PrP). It is a cell surface glycoprotein.<br />
<br />
==Structure of Dpl==<br />
<br />
{{STRUCTURE_1lg4 | PDB=1lg4 | SCENE= }}<br />
Dpl has the same fold as PrP, with three alpha helices and two short beta strands, however it differs in that the third helix has a significant kink in it and it also contains two disulphide bonds.<br />
<br />
=Related structures=<br />
* [[1z65]] Mouse Dpl residues 1-30<br />
* [[1lg4]] Human Dpl residues 24-152<br />
* [[1i17]] Mouse Dpl residues 51-157<br />
* [[1h0l]] Human PrP residues 121-230, with an additional disulphide bond analogous to the homolog [[Doppel]]<br />
<br />
<br />
=References=<br />
{{Reflist}} <br />
Moore ''et al.'' (1999) Ataxia in Prion Protein (PrP)-deficient Mice is <br />
Associated with Upregulation of the Novel PrP-like <br />
Protein Doppel ''J. Mol. Biol.'' '''292''', 797-817 </reference><br />
Zahn R. et al. (2003) NMR structure of a variant human prion protein with two disulfide bridges'' J. Mol. Biol.'' '''326''', 225-34.</div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=809206Prion protein2008-12-14T12:18:44Z<p>Kurt Giles: </p>
<hr />
<div>The prion protein (PrP) is a cell surface glycoprotein. PrP can exist in two alternatively folded confirmations: the cellular isoform (PrP<sup>C</sup>) can undergo a structural conversion to a 'scrapie' or disease associated isoform termed PrP<sup>Sc</sup>. Prion diseases such as Creutzfeldt Jakob disease (CJD) in people, and bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, are characterterized by aggregates of PrP<sup>Sc</sup>, which arise from autocatalytic refolding of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
=Structure of PrP<sup>C</sup>=<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE= }}<br />
PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230, with a single disulfide bond. The presence of the N-terminus has little impact on the structure of the C-terminal domain <ref>1</ref>.<br />
<br />
The structure is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians.<br />
<br />
ALthough having a similar overall fold, the X-ray structure of sheep PrP was dimeric <br />
<br />
=Models of PrP<sup>Sc</sup> structure=<br />
Circular dichroism studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><br />
<br />
There are a number of technical obstacles in determining the molecular structure of PrP(sup)Sc</sup><br />
<br />
<ref>10</ref><br />
<br />
=Genetic prion diseases=<br />
A number of mutations in PrP have been identified which correlate with a high incidence of prion disease. The structure of HuPrP,E200K was determined nd shown to be To date, structural studies of all mutant PrP<sup>C</sup> have extremely similar structures to wild type PrP<sup>C</sup>, suggesting a kinetic basis for the difference in converting to PrP<sup>Sc</sup>.<br />
<br />
=Prion strains=<br />
The strain phenomenon of prions ( ) was initially difficult to equate with the <br />
<br />
<br />
=Selected PrP structures=<br />
All structures determined by NMR unless otherwise specified<br />
==Human PrP==<br />
* [[1qlx]] HuPrP residues 23-230 <br />
* [[1qm0]] HuPrP residues 90-230 <br />
* [[1qm2]] HuPrP residues 121-230 <br />
* [[1i4m]] HuPrP residues 119-226 (determined by X-ray crystallography) <br />
* [[1fkc]] HuPrP,E200K residues 90-231 (genetic prion disease)<br />
* [[1h0l]] HuPrP residues 121-230, with an additional disulphide bond analogous to the homolog [[Doppel]]<br />
<br />
==Other species PrPs==<br />
* [[1xyx]] Mouse PrP residues <br />
* [[1b10]] Syrian hamster PrP residues 90-231<br />
* [[1dwy]] Cow PrP residues 121-230<br />
* [[1uw3]] Sheep PrP (determined by X-ray crystallography)<br />
* [[1xu0]] Frog PrP residues 98-226<br />
* [[1u3m]] Chicken PrP<br />
* [[1u5l]] Turtle PrP residues 121-226<br />
<br />
=References=<br />
{{Reflist}} <br />
Zahn, R. ''et al.'' (2000) NMR solution structure of the human prion protein ''Proc. Natl. Acad. Sci. USA'' '''97''', 145-150 <br />
Zahn R. et al. (2003) NMR structure of a variant human prion protein with two disulfide bridges'' J. Mol. Biol.'' '''326''', 225-34.<br />
<references/></div>Kurt Gileshttps://proteopedia.org/index.php?title=Doppel&diff=809205Doppel2008-12-14T12:01:02Z<p>Kurt Giles: New page: Doppel (Dpl), named for '''''do'''wnstream '''p'''rion '''p'''rotein like''<ref>1</ref>, is a homolog of the prion protein (PrP). It is a cell surface glycoprotein. ==Structure of Dpl...</p>
<hr />
<div>Doppel (Dpl), named for '''''do'''wnstream '''p'''rion '''p'''rotein like''<ref>1</ref>, is a homolog of the [[prion protein]] (PrP). It is a cell surface glycoprotein.<br />
<br />
==Structure of Dpl==<br />
<br />
{{STRUCTURE_1lg4 | PDB=1lg4 | SCENE= }}<br />
Dpl has the same fold as PrP, with three alpha helices and two short beta strands, however it differs in that the third helix has a significant kink in it and it also contains two disulphide bonds.<br />
<br />
=References=<br />
<br />
Moore ''et al.'' (1999) Ataxia in Prion Protein (PrP)-deficient Mice is <br />
Associated with Upregulation of the Novel PrP-like <br />
Protein Doppel ''J. Mol. Biol.'' '''292''', 797-817</div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=809204Prion protein2008-12-14T11:44:10Z<p>Kurt Giles: </p>
<hr />
<div>The prion protein (PrP) is a cell surface glycoprotein. PrP can exist in two alternatively folded confirmations: the cellular isoform (PrP<sup>C</sup>) can undergo a structural conversion to a 'scrapie' or disease associated isoform termed PrP<sup>Sc</sup>. Prion diseases such as Creutzfeldt Jakob disease (CJD) in people, and bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, are characterterized by aggregates of PrP<sup>Sc</sup>, which arise from autocatalytic refolding of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
=Structure of PrP<sup>C</sup>=<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE= }}<br />
PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230, with a single disulfide bond. The presence of the N-terminus has little impact on the structure of the C-terminal domain <ref>1</ref>.<br />
<br />
The structure is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians.<br />
<br />
ALthough having a similar overall fold, the X-ray structure of sheep PrP was dimeric <br />
<br />
=Models of PrP<sup>Sc</sup> structure=<br />
Circular dichroism studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><br />
<br />
There are a number of technical obstacles in determining the molecular structure of PrP(sup)Sc</sup><br />
<br />
=Genetic prion diseases=<br />
A number of mutations in PrP have been identified which correlate with a high incidence of prion disease. The structure of HuPrP,E200K was determined nd shown to be To date, structural studies of all mutant PrP<sup>C</sup> have extremely similar structures to wild type PrP<sup>C</sup>, suggesting a kinetic basis for the difference in converting to PrP<sup>Sc</sup>.<br />
<br />
=Prion strains=<br />
The strain phenomenon of prions ( ) was initially difficult to equate with the <br />
<br />
<br />
=Selected PrP structures=<br />
All structures determined by NMR unless otherwise specified<br />
==Human PrP==<br />
* [[1QLX]] HuPrP residues 23-230 <br />
* [[1QM0]] HuPrP residues 90-230 <br />
* [[1QM2]] HuPrP residues 121-230 <br />
* [[1I4M]] HuPrP residues 119-226 (X-ray) <br />
* [[1FKC]] HuPrP,E200K residues 90-231 (genetic prion disease)<br />
* [[1H0L]] HuPrP residues 121-230, with an additional disulphide bond analogous to the homolog Doppel<br />
<br />
==Other species PrPs==<br />
* XXXX Mouse PrP R <br />
* [[1B10]] Syrian hamster PrP residues 90-231<br />
* [[1DWY]] Cow PrP residues 121-230<br />
* [[1UW3]] Sheep PrP (X ray)<br />
* XXXX Frog PrP<br />
* XXXX Chicken PrP<br />
* XXXX Turtle PrP<br />
<br />
=References=<br />
{{Reflist}} <references/><br />
1.</div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=809201Prion protein2008-12-14T11:35:44Z<p>Kurt Giles: </p>
<hr />
<div>The prion protein (PrP) is a cell surface glycoprotein. PrP can exist in two alternatively folded confirmations: the cellular isoform (PrP<sup>C</sup>) can undergo a structural conversion to a 'scrapie' or disease associated isoform termed PrP<sup>Sc</sup>. Prion diseases such as Creutzfeldt Jakob disease (CJD) in people, and bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, are characterterized by aggregates of PrP<sup>Sc</sup>, which arise from autocatalytic refolding of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
=Structure of PrP<sup>C</sup>=<br />
PrP<sup>C</sup> has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230. <br />
<br />
The N-terminal region can bind coper ions<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE= }}<br />
<br />
The structure is highly conserved amongst mammals, and only differs slightly in birds, reptiles and amphibians.<br />
<br />
The X-ray structure of sheep PrP was dimeric...<br />
<br />
=Models of PrP<sup>Sc</sup> structure=<br />
Circular dichroism studies first demonstrated that PrP<sup>Sc</sup> had very different proportions of α-helices and β-sheet to PrP<sup>C</sup><br />
<br />
There are a number of technical obstacles in determining the molecular structure of PrP(sup)Sc</sup><br />
<br />
=Genetic prion diseases=<br />
A number of mutations in PrP have been identified which correlate with a high incidence of prion disease. To date, structural studies of all mutant PrP<sup>C</sup> have extremely similar structures to wild type PrP<sup>C</sup>, suggesting a kinetic basis for the difference in converting to PrP<sup>Sc</sup>.<br />
<br />
=Prion strains=<br />
The strain phenomenon of prions ( ) was initially difficult to equate with the <br />
<br />
<br />
=Selected PrP structures=<br />
All structures determined by NMR unless otherwise specified<br />
==Human PrP==<br />
* [[1QLX]] HuPrP residues 23-230 <br />
* [[1QM0]] HuPrP residues 90-230 <br />
* [[1QM2]] HuPrP residues 121-230 <br />
* [[1I4M]] HuPrP residues 119-226 (X-ray) <br />
* [[1E1J]] HuPrP,M166V residues 125-228<br />
* [[1E1S]] HuPrP,S170N residues 125-228<br />
* [[1E1W]] HuPrP,R220K residues 125-228<br />
* [[1FKC]] HuPrP,E200K residues 90-231 (genetic prion disease)<br />
* [[1H0L]] HuPrP residues 121-230, with an additional disulphide bond analogous to the homolog Doppel<br />
<br />
==Other species PrPs==<br />
* XXXX Mouse PrP R <br />
* [[1B10]] Syrian hamster PrP residues 90-231<br />
* [[1DWY]] Cow PrP residues 121-230<br />
* [[1UW3]] Sheep PrP (X ray)<br />
* XXXX Frog PrP<br />
* XXXX Chicken PrP<br />
* XXXX Turtle PrP<br />
<br />
=References=</div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=808780Prion protein2008-12-10T14:20:31Z<p>Kurt Giles: </p>
<hr />
<div>The prion protein (PrP) is a cell surface glycoprotein. The cellular isoform (PrP<sup>C</sup>) has a natively unstructured N-terminal region, and a predominantly α-helical C-terminal region from residues ~120-230. PrP<sup>C</sup> can undergo a structural conversion to a β-sheet rich conformation, termed PrP<sup>Sc</sup>. Prion diseases such as Creutzfeldt Jakob disease (CJD) in people, and bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, are characterterized by aggregates of PrP<sup>Sc</sup>, which arise from autocatalytic refolding of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
=Structure of PrP<sup>C</sup>=<br />
<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE= }}<br />
<br />
The structure is highly conserved amongst mammals...<br />
<br />
The X-ray structure of sheep PrP was dimeric...<br />
<br />
=Models of PrP<sup>Sc</sup> structure=<br />
There are a number of technical obstacles in determining the molecular structure of PrP(sup)Sc</sup><br />
<br />
=Selected PrP structures=<br />
All structures determined by NMR unless otherwise specified<br />
==Human PrP==<br />
* [[1QLX]] HuPrP 23-230 <br />
* [[1QM0]] HuPrP 90-230 <br />
* [[1QM2]] HuPrP 121-230 <br />
* [[1I4M]] HuPrP 119-226 (X-ray) <br />
* [[1E1J]] HuPrP,M166V 125-228 Average 125-228<br />
* [[1E1S]] HuPrP,S170N 125-228 Average 125-228<br />
* [[1E1W]] HuPrP,R220K 125-228 Average 125-228<br />
* [[1FKC]] HuPrP,E200K residues 90-231 (genetic prion disease)<br />
* [[1H0L]] HuPrP residues 121-230, with an additional disulphide bond analogous to the homolog Doppel<br />
<br />
==Other PrPs==<br />
* XXXX Mouse PrP determined by NMR <br />
* [[1B10]] Syrian hamster PrP 90-231 NMR ensemble of 25 structures<br />
* [[1DWY]] Cow PrP 121-230 Average 124-227<br />
* [[1UW3]] Sheep PrP (X ray)<br />
* XXXX Frog PrP<br />
* XXXX Chicken PrP<br />
* XXXX Turtle PrP<br />
<br />
=References=</div>Kurt Gileshttps://proteopedia.org/index.php?title=User_talk:Kurt_Giles&diff=806873User talk:Kurt Giles2008-12-09T16:18:20Z<p>Kurt Giles: New page: Should I have made this change?</p>
<hr />
<div>Should I have made this change?</div>Kurt Gileshttps://proteopedia.org/index.php?title=Sandbox1&diff=806872Sandbox12008-12-09T16:16:33Z<p>Kurt Giles: Undo revision 806871 by Kurt Giles (Talk)</p>
<hr />
<div>Human Glutamine Synthetase Tertiary Structure: Pfam domains<br />
<br />
The active site of Glutamine synthetase is the result of the interactions between two adjacent subunits.<br />
Each Subunits contains two two ends, the C-terminus and the N-terminus. The Glutamine synthetase beta grasp domain(N-terminus), and the Glutamine synthetase catalytic domain (the C-terminus). In order to stabilize the molecule, the two domains are involved in the Van Der Walls , Hydrogen . The Beta Grasp domain interact with the C-terminus of the next subunit.the two domains are proceeded by a meander of 3-24 residues that link the chains in the proteins core. <br />
<br />
Beta Grasp domain (N-terminus) <br />
-comprised of residues 43-123<br />
-binds glutamate, ammonia, and ATP<br />
<show protein alignment image><br />
<show structure of the domain in viewer><br />
<br />
Catalytic domain (C-terminus)<br />
-comprised of residues 129-382<br />
-how it functions is not described, more research is necessary here<br />
<br />
<show alignment image><br />
<show structure of the domain in viewer><br />
<br />
Active site<br />
-there are 10 active sites in the decamer of the protein, each formed from the beta grasp domain of one chain and the catalytic domain of the neighboring chain. <br />
<show relation between chains, domains, and active sites with viewer><br />
-describe visually the important aspects of the active site<br />
<show active site and ligands relationship, may need multiple scenes></div>Kurt Gileshttps://proteopedia.org/index.php?title=Sandbox1&diff=806871Sandbox12008-12-09T16:12:30Z<p>Kurt Giles: </p>
<hr />
<div>This is a new sentence. [[Prions]]<br />
<br />
<br />
Human Glutamine Synthetase Tertiary Structure: Pfam domains<br />
<br />
The active site of Glutamine synthetase is the result of the interactions between two adjacent subunits.<br />
Each Subunits contains two two ends, the C-terminus and the N-terminus. The Glutamine synthetase beta grasp domain(N-terminus), and the Glutamine synthetase catalytic domain (the C-terminus). In order to stabilize the molecule, the two domains are involved in the Van Der Walls , Hydrogen . The Beta Grasp domain interact with the C-terminus of the next subunit.the two domains are proceeded by a meander of 3-24 residues that link the chains in the proteins core. <br />
<br />
Beta Grasp domain (N-terminus) <br />
-comprised of residues 43-123<br />
-binds glutamate, ammonia, and ATP<br />
<show protein alignment image><br />
<show structure of the domain in viewer><br />
<br />
Catalytic domain (C-terminus)<br />
-comprised of residues 129-382<br />
-how it functions is not described, more research is necessary here<br />
<br />
<show alignment image><br />
<show structure of the domain in viewer><br />
<br />
Active site<br />
-there are 10 active sites in the decamer of the protein, each formed from the beta grasp domain of one chain and the catalytic domain of the neighboring chain. <br />
<show relation between chains, domains, and active sites with viewer><br />
-describe visually the important aspects of the active site<br />
<show active site and ligands relationship, may need multiple scenes></div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=806870Prion protein2008-12-09T12:55:20Z<p>Kurt Giles: </p>
<hr />
<div>The prion protein (PrP) is a cell surface glycoprotein. The cellular isoform (PrP<sup>C</sup>) has two dominas: an dN-terminal region that is natively unstructured, and a C-terminal region from residues ~120-230, which is predominantly α-helical. PrP<sup>C</sup> can undergo a structural conversion to a β-sheet rich conformation, termed PrP<sup>Sc</sup>. Prion diseases such as Creutzfeldt Jakob disease (CJD) in people, and bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, are characterterized by aggregates of PrP<sup>Sc</sup>, which arise from autocatalytic refolding of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
=Structure of PrP<sup>C</sup>=<br />
<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE= }}<br />
<br />
The structure is highly conserved amongst mammals...<br />
<br />
The X-ray structure of sheep PrP was dimeric...<br />
<br />
=Models of PrP<sup>Sc</sup> structure=<br />
There are a number of technical obstacles in determining the molecular structure of PrP(sup)Sc</sup><br />
<br />
=Selected PrP structures=<br />
==Human PrP==<br />
* [[1QLX]] HuPrP 23-230 Average 125-228<br />
* [[1QM0]] HuPrP 90-230 Average 125-228<br />
* [[1QM2]] HuPrP 121-230 Average 125-228<br />
* [[1I4M]] HuPrP 119-226 (X-ray) 119-226<br />
* [[1E1J]] HuPrP,M166V 125-228 Average 125-228<br />
* 1E1S HuPrP,S170N 125-228 Average 125-228<br />
* 1E1W HuPrP,R220K 125-228 Average 125-228<br />
* 1FKC HuPrP,E200K 90-231 Average 125-231<br />
* 1H0L HuPrP,M166C,E221C 121-230 20 structures 119-230<br />
<br />
==Other PrPs==<br />
* XXXX Mouse PrP determined by NMR <br />
<br />
* [[1B10]] Syrian hamster PrP 90-231 NMR ensemble of 25 structures<br />
* [[1DWY]] Cow PrP 121-230 Average 124-227<br />
* [[1UW3]] Sheep PrP<br />
* XXXX Frog PrP<br />
* XXXX Chicken PrP<br />
* XXXX Turtle PrP<br />
<br />
=References=</div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=806869Prion protein2008-12-09T12:50:01Z<p>Kurt Giles: </p>
<hr />
<div>The prion protein (PrP) is a cell surface glycoprotein. The cellular isoform (PrP<sup>C</sup>) has two dominas: an dN-terminal region that is natively unstructured, and a C-terminal region from residues ~120-230, which is predominantly α-helical. PrP<sup>C</sup> can undergo a structural conversion to a β-sheet rich conformation, termed PrP<sup>Sc</sup>. Prion diseases such as Creutzfeldt Jakob disease (CJD) in people, and bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, are characterterized by aggregates of PrP<sup>Sc</sup>, which arise from autocatalytic refolding of PrP<sup>C</sup> in a template-dependent manner.<br />
<br />
==Structure of PrP<sup>C</sup>==<br />
<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE= }}<br />
<br />
The structure is highly conserved amongst mammals...<br />
<br />
The X-ray structure of sheep PrP was dimeric...<br />
<br />
==Models of PrP<sup>Sc</sup> structure==<br />
There are a number of technical obstacles in determining the molecular structure of PrP(sup)Sc</sup><br />
<br />
==Selected PrP structures==<br />
=Human PrP=<br />
* [[1QLX]] HuPrP 23-230 Average 125-228<br />
* [[1QM0]] HuPrP 90-230 Average 125-228<br />
* [[1QM2]] HuPrP 121-230 Average 125-228<br />
* [[1I4M]] HuPrP 119-226 (X-ray) 119-226<br />
* [[1E1J]] HuPrP,M166V 125-228 Average 125-228<br />
* 1E1S HuPrP,S170N 125-228 Average 125-228<br />
* 1E1W HuPrP,R220K 125-228 Average 125-228<br />
* 1FKC HuPrP,E200K 90-231 Average 125-231<br />
* 1H0L HuPrP,M166C,E221C 121-230 20 structures 119-230<br />
<br />
=Other PrPs=<br />
=Rodent PrP=<br />
* XXXX Mouse PrP determined by NMR <br />
<br />
* 1B10 Syrian hamster PrP 90-231 NMR ensemble of 25 structures<br />
1DWY Cow PrP 121-230 Average 124-227<br />
1UW3 Sheep PrP<br />
* XXXX Frog PrP<br />
* XXXX Chicken PrP<br />
* XXXX Turtle PrP<br />
<br />
==References==</div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=806868Prion protein2008-12-09T12:45:37Z<p>Kurt Giles: </p>
<hr />
<div>The prion protein (PrP) is a cell surface glycoprotein. The cellular isoform (PrP<sup>C</sup>) has two dominas: an dN-terminal region that is natively unstructured, and a C-terminal region from residues ~120-230, which is predominantly α-helical. PrP<sup>C</sup> can undergo a structural conversion to a β-sheet rich conformation, termed PrP<sup>Sc</sup>. Prion diseases such as Creutzfeldt Jakob disease (CJD) in people, and bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, are characterterized by aggregates of PrP<sup>Sc</sup>, which arise from autocatalytic refolding of PrP<sup>C</sup> in a template-dependent manner.<br />
Structure from a <br />
<br />
's normal cellular function is debated, and "knockout" mice lacking PrP are phenotypically normal.<br />
<br />
has a predominantly α-helical structure and is localized to the outer leaflet of the cell membrane by a glycolipid anchor. In prion diseases PrPC undergoes a major structural transformation converting . This process is autocatalytic with PrPSc driving the refolding of PrPC in a template-dependent manner, leading to accumulation of PrPSc and ultimately neuronal cell death.<br />
<br />
==Structure of PrPC==<br />
<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE= }}<br />
<br />
<br />
<br />
==Selected PrP structures==<br />
=Human PrP=<br />
* 1QLX HuPrP 23-230 Average 125-228<br />
* 1QM0 HuPrP 90-230 Average 125-228<br />
* 1QM2 HuPrP 121-230 Average 125-228<br />
* 1I4M HuPrP 119-226 (X-ray) 119-226<br />
* 1E1J HuPrP,M166V 125-228 Average 125-228<br />
* 1E1S HuPrP,S170N 125-228 Average 125-228<br />
* 1E1W HuPrP,R220K 125-228 Average 125-228<br />
* 1FKC HuPrP,E200K 90-231 Average 125-231<br />
* 1H0L HuPrP,M166C,E221C 121-230 20 structures 119-230<br />
<br />
=Other PrPs=<br />
=Rodent PrP=<br />
* XXXX Mouse PrP determined by NMR <br />
<br />
* 1B10 Syrian hamster PrP 90-231 NMR ensemble of 25 structures<br />
1DWY Cow PrP 121-230 Average 124-227<br />
1UW3 Sheep PrP<br />
* XXXX Frog PrP<br />
* Chicken PrP<br />
* Turtle PrP</div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=806867Prion protein2008-12-09T10:55:15Z<p>Kurt Giles: </p>
<hr />
<div>The prion protein (PrP) is a cell surface glycoprotein. The cellular isoform (PrP<sup>C</sup>) is predominantly α-helical, but can undergo a structural conversion to a β-sheet rich conformation, termed PrP<sup>Sc</sup>. Prion diseases such as Creutzfeldt Jakob disease (CJD) in people, and bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, are characterterized by aggregates of PrP<sup>Sc</sup>, which arise from autocatalytic refolding of PrP<sup>C</sup> in a template-dependent manner.<br />
Structure from a <br />
<br />
's normal cellular function is debated, and "knockout" mice lacking PrP are phenotypically normal.<br />
<br />
has a predominantly α-helical structure and is localized to the outer leaflet of the cell membrane by a glycolipid anchor. In prion diseases PrPC undergoes a major structural transformation converting . This process is autocatalytic with PrPSc driving the refolding of PrPC in a template-dependent manner, leading to accumulation of PrPSc and ultimately neuronal cell death.<br />
<br />
==Structure of PrPC==<br />
<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE= }}<br />
<br />
<br />
<br />
==PrP structures==<br />
1AG2 Mouse PrP 121-231 determined by NMR <br />
1B10 Syrian hamster PrP 90-231 NMR ensemble of 25 structures<br />
1DWY BoPrP 121-230 Average 124-227<br />
1DWZ BoPrP 121-230 20 structures 124-227<br />
1DX0 BoPrP 23-230 Average 124-227<br />
1DX1 BoPrP 23-230 20 structures 124-227<br />
1E1G HuPrP,M166V 125-228 20 structures 125-228<br />
1E1J HuPrP,M166V 125-228 Average 125-228<br />
1E1P HuPrP,S170N 125-228 20 structures 125-228<br />
1E1S HuPrP,S170N 125-228 Average 125-228<br />
1E1U HuPrP,R220K 125-228 20 structures 125-228<br />
1E1W HuPrP,R220K 125-228 Average 125-228<br />
1FKC HuPrP,E200K 90-231 Average 125-231<br />
1FO7 HuPrP,E200K 90-231 30 structures 125-231<br />
1HJM HuPrP Average<br />
1HJN HuPrP 20 structures<br />
1H0L HuPrP,M166C,E221C 121-230 20 structures 119-230<br />
1I4M HuPrP 119-226 (X-ray) 119-226<br />
1QLX HuPrP 23-230 Average 125-228<br />
1QLZ HuPrP 23-230 20 structures 125-228<br />
1QM0 HuPrP 90-230 Average 125-228<br />
1QM1 HuPrP 90-230 20 structures 125-228<br />
1QM2 HuPrP 121-230 Average 125-228<br />
1QM3 HuPrP 121-230 20 structures 125-228<br />
1UW3 OvPrP</div>Kurt Gileshttps://proteopedia.org/index.php?title=Prion_protein&diff=806866Prion protein2008-12-09T10:44:09Z<p>Kurt Giles: New page: The prion protein (PrP) is a cell surface glycoprotein. The cellular isoform (PrPC) is predominantly α-helical, but can undergo a structural conversion to a β-sheet rich conformation, te...</p>
<hr />
<div>The prion protein (PrP) is a cell surface glycoprotein. The cellular isoform (PrPC) is predominantly α-helical, but can undergo a structural conversion to a β-sheet rich conformation, termed PrPSc. Prion diseases such as Creutzfeldt Jakob disease (CJD) in people, and bovine spongiform encephalopathy (BSE) commonly known as "mad cow" disease, are characterterized by aggregates of PrPSc<br />
<br />
's normal cellular function is debated, and "knockout" mice lacking PrP are phenotypically normal.<br />
<br />
has a predominantly α-helical structure and is localized to the outer leaflet of the cell membrane by a glycolipid anchor. In prion diseases PrPC undergoes a major structural transformation converting . This process is autocatalytic with PrPSc driving the refolding of PrPC in a template-dependent manner, leading to accumulation of PrPSc and ultimately neuronal cell death.<br />
<br />
==Structure of PrPC==<br />
<br />
{{STRUCTURE_1hjm | PDB=1hjm | SCENE= }}</div>Kurt Giles