Proteopedia - User contributions [en]

Sandbox 210

2011-12-31T18:27:33Z

Pascaline Menou:

===CDK5-p25 complex===

[[Image:1h4l.jpg|left|200px]]
{{STRUCTURE_1h4l| PDB=1h4l | SCENE= }}

== CDK5 – Cyclin dependent Kinase 5 ==

CDK5 is a serine-threonine kinase belonging to a large protein family: the '''cyclin dependent kinases'''. CDK5 gene has been mapped to chromosome seven. This CDK5 protein is a 33 kDa molecule with kinase activity when bound to its activators. Also known as proline-directed kinase, activated CDK5 phosphorylates the amino acids serine and threonine of its substrate that have a proline immediately downstream at position +1. The phosphorylation motif of CDK5's substrate is S/TPXK/R where S/T stands for serine respectively threonine, X can be any amino acid, P represents the obligatory proline and K/R stands for lysine or arginine, which are preferred at downstream position +3. Cyclin dependent kinases play a crucial role in the regulation of the eukaryotic cell cycle. Since CDK5 plays only little role in cell cycle regulation processes, it is an unusual member of this protein family.
It is rather involved in cell-cell communication, cell morphology and motility, and is indispensable for a correct neural development.<ref name="un">DOI 10.1007/s10571-007-9242-1</ref> CDK5 was identified as member of the CDK-family because of its 58 % sequence homology with mouse CDK1 and its 61 % sequence homology with human CDK2.<ref name="discovery">PMID:1279696</ref> Whereas CDKs are activated upon association with specific cyclins, the kinase activity of CDK5 is activated by its association with non-cyclin molecules such as p25, p35 or p39.<ref>doi:10.1038/371423a0</ref><ref>PMID:7592934</ref>

==History==

Reported by four independent groups of scientists in 1992, CDK5 had multiple names. A first group reported it as a neuronal CDC2 like kinase (NCLK) characterized and cloned from rat brain c-DNA library as a CDK that phosphorylates the lysine–serine–proline motif of neurofilaments. It was reported to have 58% amino acid sequence homology with mouse CDK1 and 61% homology with human CDK2.<ref name="discovery" /> While looking for several CDKs, which play an important role in eukaryotic cell cycle, a second group found CDK5/PSSALARE kinase (with an alpha C helix) among several other CDKs.<ref>PMID: 1639063</ref> A third group of scientists called the same molecule as brain proline-directed protein kinase (BPDK), reporting it in bovine brain with functional similarity to CDC2.<ref>PMID: 1618840</ref> In the same year, the fourth group named it as Tau protein kinase II (TPK II) associated with microtubules.<ref>PMID: 1587865 </ref> Later in 1993, the nomenclature settled down to CDK5 after identifying the 30 kDa protein subunit of the active enzyme.<ref>PMID: 8253190</ref>

==Structure==

The 33 kDa- protein CDK5 consists of an eukaryotic catalytic domain (ePK) that is flanked by other domains involved in the regulation of ePK. CDK5 consists of a C-terminal domain that shows alpha-helical structure (C-lobe) and an N-terminal domain (N-lobe) consisting predominantly of a beta-sheet but also containing an alpha-helix, named alpha C-helix or PSAALRE, based on its amino acid sequence. Between N- and C-lobe the ATP-binding site is located in a deep cleft. Structural changes of the ePK domain are leading to different activation states of the kinase. Only a unique active conformation is able to transfer phosphate from an ATP-molecule onto a substrate. The activation loop or T-loop, a flexible stretch of approximately 20 amino acids between the interface of the C- and N-lobes, is the key for the control of these conformational changes. It provides the association of CDK5 with its activator proteins and is involved in the positioning of ATP. The activator protein of CDK5, p25, presents a cyclin-box fold domain, which is the structural motif found in the cyclins. More precisely, CDK5 binds p25 through its single cyclin box fold (CBF) around the CDK5's PSAALRE helix and the activation loop. The subunit of the CDK5 shares also a very similar three-dimensional (3D) structure with CDK2.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>
Analyses of the crystal structures of CDK5/p25 show the existence of extensive electrostatic and Van Der Waals interactions between the β sheet, and a small loop following the C helix (f-loop) of CDK5, and an helix of p25.
During the unbinding processes between CDK5 and p25, obvious conformational changes in the C helix and the T loop are observed. The C helix, together with the loop preceding the helix (the p-loop) apparently displaces from its original location towards the p25 side. The distances between the C-alpha carbon atoms of the tip amino acid of the p-loop (Gly43) and the starting amino acid of the C helix (Ser46) before and after pulling are 14.15 Å and 7.23 Å, respectively.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>

===Sequence similarities===
The <scene name='Sandbox_210/1h4l_chainsab/2'>chains A and B</scene> of the CDK5-p25 complex share homologuous sequences with the cell division protein kinase 5 and the <scene name='Sandbox_210/1h4l_chainsde/1'>chains D and E</scene> with the cyclin-dependent kinase 5 activator (p35).

==Biology==

===Physiological functions of CDK5===

CDK5 is in several aspects important for neuronal development. It is implicated in cytoskeleton assembly and organization during axonal growth, neuronal differentiation and migration, synaptic activities in mature neurons and cell death in neurodegenerative diseases. CDK5 is also involved in the regulation of exocytosis and endocytosis of synaptic vesicles. It modulates signal transduction pathways regulating neuronal survival.<ref>PMID: 11248668</ref> CDK5 is implicated in Alzheimer’s disease as it is involved in the hyperphosphorylation of the protein Tau that leads to neuronal cell death.

===CDK5-p25 complex Control===

Sometimes, p35, an activator of CDK5, is cleaved in p25 by a protease calcium-dependent, the calpain. This cut form of p35 (p25) is able to activate CDK5 and to trigger a modification of its cellular localization. It can increase its activity too. In Alzheimer’s disease or in the amyotrophic lateral sclerosis (ALS), when the ratio of p25 over p35 increases, it leads to hyperactivity of CDK5 which could hyperphosphorylate the protein Tau. The neurotoxic activator p25 activates CDK5 in one step by tethering the T-loop in the extended conformation and exposing CDK5's active site for kinase activity. When activated by p25, CDK5 causes the death of neurons, leading to neurodegenerative diseases. Deregulation of CDK5 has been implicated in Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Huntington’s disease and acute neuronal injury. Regulators of CDK5 activity are considered as potential therapeutic molecules for degenerative diseases.<ref name="un" />

==External Resource==
*[http://www.rcsb.org/pdb/explore.do?structureId=1h4l Protein Data Bank file on 1H4L]

==References==
<references />

==Proteopedia Page Contributors and Editors==

Stephanie Müller, Pascaline Menou

Sandbox 210

2011-12-31T18:26:55Z

Pascaline Menou:

===CDK5-p25 complex===

[[Image:1h4l.jpg|left|200px]]
{{STRUCTURE_1h4l| PDB=1h4l | SCENE= }}

== CDK5 – Cyclin dependent Kinase 5 ==

CDK5 is a serine-threonine kinase belonging to a large protein family: the '''cyclin dependent kinases'''. CDK5 gene has been mapped to chromosome seven. This CDK5 protein is a 33 kDa molecule with kinase activity when bound to its activators. Also known as proline-directed kinase, activated CDK5 phosphorylates the amino acids serine and threonine of its substrate that have a proline immediately downstream at position +1. The phosphorylation motif of CDK5's substrate is S/TPXK/R where S/T stands for serine respectively threonine, X can be any amino acid, P represents the obligatory proline and K/R stands for lysine or arginine, which are preferred at downstream position +3. Cyclin dependent kinases play a crucial role in the regulation of the eukaryotic cell cycle. Since CDK5 plays only little role in cell cycle regulation processes, it is an unusual member of this protein family.
It is rather involved in cell-cell communication, cell morphology and motility, and is indispensable for a correct neural development.<ref name="un">DOI 10.1007/s10571-007-9242-1</ref> CDK5 was identified as member of the CDK-family because of its 58 % sequence homology with mouse CDK1 and its 61 % sequence homology with human CDK2.<ref name="discovery">PMID:1279696</ref> Whereas CDKs are activated upon association with specific cyclins, the kinase activity of CDK5 is activated by its association with non-cyclin molecules such as p25, p35 or p39.<ref>doi:10.1038/371423a0</ref><ref>PMID:7592934</ref>

==History==

Reported by four independent groups of scientists in 1992, CDK5 had multiple names. A first group reported it as a neuronal CDC2 like kinase (NCLK) characterized and cloned from rat brain c-DNA library as a CDK that phosphorylates the lysine–serine–proline motif of neurofilaments. It was reported to have 58% amino acid sequence homology with mouse CDK1 and 61% homology with human CDK2.<ref name="discovery" /> While looking for several CDKs, which play an important role in eukaryotic cell cycle, a second group found CDK5/PSSALARE kinase (with an alpha C helix) among several other CDKs.<ref>PMID: 1639063</ref> A third group of scientists called the same molecule as brain proline-directed protein kinase (BPDK), reporting it in bovine brain with functional similarity to CDC2.<ref>PMID: 1618840</ref> In the same year, the fourth group named it as Tau protein kinase II (TPK II) associated with microtubules.<ref>PMID: 1587865 </ref> Later in 1993, the nomenclature settled down to CDK5 after identifying the 30 kDa protein subunit of the active enzyme.<ref>PMID: 8253190</ref>

==Structure==

The 33 kDa- protein CDK5 consists of an eukaryotic catalytic domain (ePK) that is flanked by other domains involved in the regulation of ePK. CDK5 consists of a C-terminal domain that shows alpha-helical structure (C-lobe) and an N-terminal domain (N-lobe) consisting predominantly of a beta-sheet but also containing an alpha-helix, named alpha C-helix or PSAALRE, based on its amino acid sequence. Between N- and C-lobe the ATP-binding site is located in a deep cleft. Structural changes of the ePK domain are leading to different activation states of the kinase. Only a unique active conformation is able to transfer phosphate from an ATP-molecule onto a substrate. The activation loop or T-loop, a flexible stretch of approximately 20 amino acids between the interface of the C- and N-lobes, is the key for the control of these conformational changes. It provides the association of CDK5 with its activator proteins and is involved in the positioning of ATP. The activator protein of CDK5, p25, presents a cyclin-box fold domain, which is the structural motif found in the cyclins. More precisely, CDK5 binds p25 through its single cyclin box fold (CBF) around the CDK5's PSAALRE helix and the activation loop. The subunit of the CDK5 shares also a very similar three-dimensional (3D) structure with CDK2.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>
Analyses of the crystal structures of CDK5/p25 show the existence of extensive electrostatic and Van Der Waals interactions between the β sheet, and a small loop following the C helix (f-loop) of CDK5, and an helix of p25.
During the unbinding processes between CDK5 and p25, obvious conformational changes in the C helix and the T loop are observed. The C helix, together with the loop preceding the helix (the p-loop) apparently displaces from its original location towards the p25 side. The distances between the C-alpha carbon atoms of the tip amino acid of the p-loop (Gly43) and the starting amino acid of the C helix (Ser46) before and after pulling are 14.15 Å and 7.23 Å, respectively.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>

===Sequence similarities===
The <scene name='Sandbox_210/1h4l_chainsab/2'>chains A and B</scene> of the CDK5-p25 complex share homologuous sequences with the cell division protein kinase 5 and the <scene name='Sandbox_210/1h4l_chainsde/1'>chains D and E</scene> with the cyclin-dependent kinase 5 activator (p35).

==Biology==

===Physiological Functions of CDK5===

CDK5 is in several aspects important for neuronal development. It is implicated in cytoskeleton assembly and organization during axonal growth, neuronal differentiation and migration, synaptic activities in mature neurons and cell death in neurodegenerative diseases. CDK5 is also involved in the regulation of exocytosis and endocytosis of synaptic vesicles. It modulates signal transduction pathways regulating neuronal survival.<ref>PMID: 11248668</ref> CDK5 is implicated in Alzheimer’s disease as it is involved in the hyperphosphorylation of the protein Tau that leads to neuronal cell death.

===CDK5-p25 complex Control===

Sometimes, p35, an activator of CDK5, is cleaved in p25 by a protease calcium-dependent, the calpain. This cut form of p35 (p25) is able to activate CDK5 and to trigger a modification of its cellular localization. It can increase its activity too. In Alzheimer’s disease or in the amyotrophic lateral sclerosis (ALS), when the ratio of p25 over p35 increases, it leads to hyperactivity of CDK5 which could hyperphosphorylate the protein Tau. The neurotoxic activator p25 activates CDK5 in one step by tethering the T-loop in the extended conformation and exposing CDK5's active site for kinase activity. When activated by p25, CDK5 causes the death of neurons, leading to neurodegenerative diseases. Deregulation of CDK5 has been implicated in Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Huntington’s disease and acute neuronal injury. Regulators of CDK5 activity are considered as potential therapeutic molecules for degenerative diseases.<ref name="un" />

==External Resource==
*[http://www.rcsb.org/pdb/explore.do?structureId=1h4l Protein Data Bank file on 1H4L]

==References==
<references />

==Proteopedia Page Contributors and Editors==

Stephanie Müller, Pascaline Menou

Sandbox 210

2011-12-31T18:24:29Z

Pascaline Menou:

===CDK5-p25 complex===

[[Image:1h4l.jpg|left|200px]]
{{STRUCTURE_1h4l| PDB=1h4l | SCENE= }}

== CDK5 – Cyclin dependent Kinase 5 ==

CDK5 is a serine-threonine kinase belonging to a large protein family: the '''cyclin dependent kinases'''. CDK5 gene has been mapped to chromosome seven. This CDK5 protein is a 33 kDa molecule with kinase activity when bound to its activators. Also known as proline-directed kinase, activated CDK5 phosphorylates the amino acids serine and threonine of its substrate that have a proline immediately downstream at position +1. The phosphorylation motif of CDK5's substrate is S/TPXK/R where S/T stands for serine respectively threonine, X can be any amino acid, P represents the obligatory proline and K/R stands for lysine or arginine, which are preferred at downstream position +3. Cyclin dependent kinases play a crucial role in the regulation of the eukaryotic cell cycle. Since CDK5 plays only little role in cell cycle regulation processes, it is an unusual member of this protein family.
It is rather involved in cell-cell communication, cell morphology and motility, and is indispensable for a correct neural development.<ref name="un">DOI 10.1007/s10571-007-9242-1</ref> CDK5 was identified as member of the CDK-family because of its 58 % sequence homology with mouse CDK1 and its 61 % sequence homology with human CDK2.<ref name="discovery">PMID:1279696</ref> Whereas CDKs are activated upon association with specific cyclins, the kinase activity of CDK5 is activated by its association with non-cyclin molecules such as p25, p35 or p39.<ref>doi:10.1038/371423a0</ref><ref>PMID:7592934</ref>

==History==

Reported by four independent groups of scientists in 1992, CDK5 had multiple names. A first group reported it as a neuronal CDC2 like kinase (NCLK) characterized and cloned from rat brain c-DNA library as a CDK that phosphorylates the lysine–serine–proline motif of neurofilaments. It was reported to have 58% amino acid sequence homology with mouse CDK1 and 61% homology with human CDK2.<ref name="discovery" /> While looking for several CDKs, which play an important role in eukaryotic cell cycle, a second group found CDK5/PSSALARE kinase (with an alpha C helix) among several other CDKs.<ref>PMID: 1639063</ref> A third group of scientists called the same molecule as brain proline-directed protein kinase (BPDK), reporting it in bovine brain with functional similarity to CDC2.<ref>PMID: 1618840</ref> In the same year, the fourth group named it as Tau protein kinase II (TPK II) associated with microtubules.<ref>PMID: 1587865 </ref> Later in 1993, the nomenclature settled down to CDK5 after identifying the 30 kDa protein subunit of the active enzyme.<ref>PMID: 8253190</ref>

==Structure==

The 33 kDa- protein CDK5 consists of an eukaryotic catalytic domain (ePK) that is flanked by other domains involved in the regulation of ePK. CDK5 consists of a C-terminal domain that shows alpha-helical structure (C-lobe) and an N-terminal domain (N-lobe) consisting predominantly of a beta-sheet but also containing an alpha-helix, named alpha C-helix or PSAALRE, based on its amino acid sequence. Between N- and C-lobe the ATP-binding site is located in a deep cleft. Structural changes of the ePK domain are leading to different activation states of the kinase. Only a unique active conformation is able to transfer phosphate from an ATP-molecule onto a substrate. The activation loop or T-loop, a flexible stretch of approximately 20 amino acids between the interface of the C- and N-lobes, is the key for the control of these conformational changes. It provides the association of CDK5 with its activator proteins and is involved in the positioning of ATP. The activator protein of CDK5, p25, presents a cyclin-box fold domain, which is the structural motif found in the cyclins. More precisely, CDK5 binds p25 through its single cyclin box fold (CBF) around the CDK5's PSAALRE helix and the activation loop. The subunit of the CDK5 shares also a very similar three-dimensional (3D) structure with CDK2.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>
Analyses of the crystal structures of CDK5/p25 show the existence of extensive electrostatic and Van Der Waals interactions between the β sheet, and a small loop following the C helix (f-loop) of CDK5, and an helix of p25.
During the unbinding processes between CDK5 and p25, obvious conformational changes in the C helix and the T loop are observed. The C helix, together with the loop preceding the helix (the p-loop) apparently displaces from its original location towards the p25 side. The distances between the C-alpha carbon atoms of the tip amino acid of the p-loop (Gly43) and the starting amino acid of the C helix (Ser46) before and after pulling are 14.15 Å and 7.23 Å, respectively.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>

===Sequence similarities===
The <scene name='Sandbox_210/1h4l_chainsab/2'>chains A and B</scene> of the CDK5-p25 complex share homologuous sequences with the cell division protein kinase 5 and the <scene name='Sandbox_210/1h4l_chainsde/1'>chains D and E</scene> with the cyclin-dependent kinase 5 activator (p35).

==Biology==

===Physiological Functions of CDK5===

CDK5 is in several aspects important for neuronal development. It is implicated in cytoskeleton assembly and organization during axonal growth, neuronal differentiation and migration, synaptic activities in mature neurons and cell death in neurodegenerative diseases. CDK5 is also involved in the regulation of exocytosis and endocytosis of synaptic vesicles. It modulates signal transduction pathways regulating neuronal survival.<ref>PMID: 11248668</ref> CDK5 is implicated in Alzheimer’s disease as it is involved in the hyperphosphorylation of the protein Tau that leads to neuronal cell death.

===Pathophysiology===

CDK5 is more and more believed to be linked to the etiopathology of neurodegenerative diseases like Alzheimer’s disease or amyotrophic lateral sclerosis (ALS).

===CDK5-p25 complex Control===

Sometimes, p35, an activator of CDK5, is cleaved in p25 by a protease calcium-dependent, the calpain. This cut form of p35 (p25) is able to activate CDK5 and to trigger a modification of its cellular localization. It can increase its activity too. In Alzheimer’s disease or in the amyotrophic lateral sclerosis, when the ratio of p25 over p35 increases, it leads to hyperactivity of CDK5 which could hyperphosphorylate the protein Tau. The neurotoxic activator p25 activates CDK5 in one step by tethering the T-loop in the extended conformation and exposing CDK5's active site for kinase activity. When activated by p25, CDK5 causes the death of neurons, leading to neurodegenerative diseases. Deregulation of CDK5 has been implicated in Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s disease and acute neuronal injury. Regulators of CDK5 activity are considered as potential therapeutic molecules for degenerative diseases.<ref name="un" />

==External Resource==
*[http://www.rcsb.org/pdb/explore.do?structureId=1h4l Protein Data Bank file on 1H4L]

==References==
<references />

==Proteopedia Page Contributors and Editors==

Stephanie Müller, Pascaline Menou

Sandbox 210

2011-12-31T18:21:07Z

Pascaline Menou:

===CDK5-p25 complex===

[[Image:1h4l.jpg|left|200px]]
{{STRUCTURE_1h4l| PDB=1h4l | SCENE= }}

== CDK5 – Cyclin dependent Kinase 5 ==

CDK5 is a serine-threonine kinase belonging to a large protein family: the '''cyclin dependent kinases'''. CDK5 gene has been mapped to chromosome seven. This CDK5 protein is a 33 kDa molecule with kinase activity when bound to its activators. Also known as proline-directed kinase, activated CDK5 phosphorylates the amino acids serine and threonine of its substrate that have a proline immediately downstream at position +1. The phosphorylation motif of CDK5's substrate is S/TPXK/R where S/T stands for serine respectively threonine, X can be any amino acid, P represents the obligatory proline and K/R stands for lysine or arginine, which are preferred at downstream position +3. Cyclin dependent kinases play a crucial role in the regulation of the eukaryotic cell cycle. Since CDK5 plays only little role in cell cycle regulation processes, it is an unusual member of this protein family.
It is rather involved in cell-cell communication, cell morphology and motility, and is indispensable for a correct neural development.<ref name="un">DOI 10.1007/s10571-007-9242-1</ref> CDK5 was identified as member of the CDK-family because of its 58 % sequence homology with mouse CDK1 and its 61 % sequence homology with human CDK2.<ref name="discovery">PMID:1279696</ref> Whereas CDKs are activated upon association with specific cyclins, the kinase activity of CDK5 is activated by its association with non-cyclin molecules such as p25, p35 or p39.<ref>doi:10.1038/371423a0</ref><ref>PMID:7592934</ref>

==History==

Reported by four independent groups of scientists in 1992, CDK5 had multiple names. A first group reported it as a neuronal CDC2 like kinase (NCLK) characterized and cloned from rat brain c-DNA library as a CDK that phosphorylates the lysine–serine–proline motif of neurofilaments. It was reported to have 58% amino acid sequence homology with mouse CDK1 and 61% homology with human CDK2.<ref name="discovery" /> While looking for several CDKs, which play an important role in eukaryotic cell cycle, a second group found CDK5/PSSALARE kinase (with an alpha C helix) among several other CDKs.<ref>PMID: 1639063</ref> A third group of scientists called the same molecule as brain proline-directed protein kinase (BPDK), reporting it in bovine brain with functional similarity to CDC2.<ref>PMID: 1618840</ref> In the same year, the fourth group named it as Tau protein kinase II (TPK II) associated with microtubules.<ref>PMID: 1587865 </ref> Later in 1993, the nomenclature settled down to CDK5 after identifying the 30 kDa protein subunit of the active enzyme.<ref>PMID: 8253190</ref>

==Structure==

The 33 kDa- protein CDK5 consists of an eukaryotic catalytic domain (ePK) that is flanked by other domains involved in the regulation of ePK. CDK5 consists of a C-terminal domain that shows alpha-helical structure (C-lobe) and an N-terminal domain (N-lobe) consisting predominantly of a beta-sheet but also containing an alpha-helix, named alpha C-helix or PSAALRE, based on its amino acid sequence. Between N- and C-lobe the ATP-binding site is located in a deep cleft. Structural changes of the ePK domain are leading to different activation states of the kinase. Only a unique active conformation is able to transfer phosphate from an ATP-molecule onto a substrate. The activation loop or T-loop, a flexible stretch of approximately 20 amino acids between the interface of the C- and N-lobes, is the key for the control of these conformational changes. It provides the association of CDK5 with its activator proteins and is involved in the positioning of ATP. The activator protein of CDK5, p25, presents a cyclin-box fold domain, which is the structural motif found in the cyclins. More precisely, CDK5 binds p25 through its single cyclin box fold (CBF) around the CDK5's PSAALRE helix and the activation loop. The subunit of the CDK5 shares also a very similar three-dimensional (3D) structure with CDK2.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>
Analyses of the crystal structures of CDK5/p25 show the existence of extensive electrostatic and Van Der Waals interactions between the β sheet, and a small loop following the C helix (f-loop) of CDK5, and an helix of p25.
During the unbinding processes between CDK5 and p25, obvious conformational changes in the C helix and the T loop are observed. The C helix, together with the loop preceding the helix (the p-loop) apparently displaces from its original location towards the p25 side. The distances between the C-alpha carbon atoms of the tip amino acid of the p-loop (Gly43) and the starting amino acid of the C helix (Ser46) before and after pulling are 14.15 Å and 7.23 Å, respectively.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>

===Sequence similarities===
The <scene name='Sandbox_210/1h4l_chainsab/2'>chains A and B</scene> of the CDK5-p25 complex share homologuous sequences with the cell division protein kinase 5 and the <scene name='Sandbox_210/1h4l_chainsde/1'>chains D and E</scene> with the cyclin-dependent kinase 5 activator (p35).

==Biology==

===Physiological Functions of CDK5===

CDK5 is in several aspects important for neuronal development. It is implicated in cytoskeleton assembly and organization during axonal growth, neuronal differentiation and migration, synaptic activities in mature neurons and cell death in neurodegenerative diseases. CDK5 is also involved in the regulation of exocytosis and endocytosis of synaptic vesicles. It modulates signal transduction pathways regulating neuronal survival.<ref>PMID: 11248668</ref> CDK5 is implicated in Alzheimer’s disease as it is involved in the hyperphosphorylation of the protein Tau that leads to neuronal cell death.

===Pathophysiology===

CDK5 is more and more believed to be linked to the etiopathology of neurodegenerative diseases like Alzheimer’s disease or amyotrophic lateral sclerosis (ALS).

===CDK5-p25 complex Control===

The neurotoxic activator p25 activates CDK5 in one step by tethering the T-loop in the extended conformation and exposing CDK5's active site for kinase activity. When activated by p25, CDK5 causes the death of neurons, leading to neurodegenerative diseases. Deregulation of CDK5 has been implicated in Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s disease and acute neuronal injury. Regulators of CDK5 activity are considered as potential therapeutic molecules for degenerative diseases. Sometimes, p35, the activator of CDK5, is cleaved in p25 by a protease calcium-dependent, the calpain. This cut form of p35 (p25) is able to activate CDK5 and to trigger a modification of its cellular localization. It can increase its activity too. In Alzheimer’s disease or in the amyotrophic lateral sclerosis, when the ratio of p25 over p35 increases, it leads to hyperactivity of CDK5 which could hyperphosphorylate the protein Tau.<ref name="un" />

==External Resource==
*[http://www.rcsb.org/pdb/explore.do?structureId=1h4l Protein Data Bank file on 1H4L]

==References==
<references />

==Proteopedia Page Contributors and Editors==

Stephanie Müller, Pascaline Menou

Sandbox 210

2011-12-31T18:08:18Z

Pascaline Menou:

===CDK5-p25 complex===

[[Image:1h4l.jpg|left|200px]]
{{STRUCTURE_1h4l| PDB=1h4l | SCENE= }}

== CDK5 – Cyclin dependent Kinase 5 ==

CDK5 is a serine-threonine kinase belonging to a large protein family: the '''cyclin dependent kinases'''. CDK5 gene has been mapped to chromosome seven. This CDK5 protein is a 33 kDa molecule with kinase activity when bound to its activators. Also known as proline-directed kinase, activated CDK5 phosphorylates the amino acids serine and threonine of its substrate that have a proline immediately downstream at position +1. The phosphorylation motif of CDK5's substrate is S/TPXK/R where S/T stands for serine respectively threonine, X can be any amino acid, P represents the obligatory proline and K/R stands for lysine or arginine, which are preferred at downstream position +3. Cyclin dependent kinases play a crucial role in the regulation of the eukaryotic cell cycle. Since CDK5 plays only little role in cell cycle regulation processes, it is an unusual member of this protein family.
It is rather involved in cell-cell communication, cell morphology and motility, and is indispensable for a correct neural development.<ref name="un">DOI 10.1007/s10571-007-9242-1</ref> CDK5 was identified as member of the CDK-family because of its 58 % sequence homology with mouse CDK1 and its 61 % sequence homology with human CDK2.<ref name="discovery">PMID:1279696</ref> Whereas CDKs are activated upon association with specific cyclins, the kinase activity of CDK5 is activated by its association with non-cyclin molecules such as p25, p35 or p39.<ref>doi:10.1038/371423a0</ref><ref>PMID:7592934</ref>

==History==

Reported by four independent groups of scientists in 1992, CDK5 had multiple names. A first group reported it as a neuronal CDC2 like kinase (NCLK) characterized and cloned from rat brain c-DNA library as a CDK that phosphorylates the lysine–serine–proline motif of neurofilaments. It was reported to have 58% amino acid sequence homology with mouse CDK1 and 61% homology with human CDK2.<ref name="discovery" /> While looking for several CDKs, which play an important role in eukaryotic cell cycle, a second group found CDK5/PSSALARE kinase (with an alpha C helix) among several other CDKs.<ref>PMID: 1639063</ref> A third group of scientists called the same molecule as brain proline-directed protein kinase (BPDK), reporting it in bovine brain with functional similarity to CDC2.<ref>PMID: 1618840</ref> In the same year, the fourth group named it as Tau protein kinase II (TPK II) associated with microtubules.<ref>PMID: 1587865 </ref> Later in 1993, the nomenclature settled down to CDK5 after identifying the 30 kDa protein subunit of the active enzyme.<ref>PMID: 8253190</ref>

==Structure==

Like most eukaryotic protein kinases, Cdk5 has a catalytic domain flanked with additional domains that are involved in its regulation. The catalytic domain has an N-terminal lobe of beta-sheet and alpha-helical C-domain (C lobe) with an ATP binding site between the two. The alpha-helical structure is called PSAALRE based on the polypeptide sequence. A stretch of 20 residues located centrally at the interphase of N and C lobe can acquire a conformation competent for phosphate transfer and is called the activation loop.<ref name="un" />
The subunit of the CDK5 shares also a very similar three-dimensional (3D) structure with CDK2.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>

The activator protein of CDK5, p25, presents a cyclin-box fold domain, which is the structural motif found in the cyclins.
Analyses of the crystal structures of CDK5/p25 show the existence of extensive electrostatic and Van Der Waals interactions between the β sheet, and a small loop following the C helix (f-loop) of CDK5, and an helix of p25.
During the unbinding processes between CDK5 and p25, obvious conformational changes in the C helix and the T loop are observed. The C helix, together with the loop preceding the helix (the p-loop) apparently displaces from its original location towards the p25 side. The distances between the C-alpha carbon atoms of the tip amino acid of the p-loop (Gly43) and the starting amino acid of the C helix (Ser46) before and after pulling are 14.15 Å and 7.23 Å, respectively.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>

===Sequence similarities===
The <scene name='Sandbox_210/1h4l_chainsab/2'>chains A and B</scene> of the CDK5-p25 complex share homologuous sequences with the cell division protein kinase 5 and the <scene name='Sandbox_210/1h4l_chainsde/1'>chains D and E</scene> with the cyclin-dependent kinase 5 activator (p35).

==Biology==

===Physiological Functions of CDK5===

CDK5 is in several aspects important for neuronal development. It is implicated in cytoskeleton assembly and organization during axonal growth, neuronal differentiation and migration, synaptic activities in mature neurons and cell death in neurodegenerative diseases. CDK5 is also involved in the regulation of exocytosis and endocytosis of synaptic vesicles. It modulates signal transduction pathways regulating neuronal survival.<ref>PMID: 11248668</ref> CDK5 is implicated in Alzheimer’s disease as it is involved in the hyperphosphorylation of the protein Tau that leads to neuronal cell death.

===Pathophysiology===

CDK5 is more and more believed to be linked to the etiopathology of neurodegenerative diseases like Alzheimer’s disease or amyotrophic lateral sclerosis (ALS).

===CDK5-p25 complex Control===

The neurotoxic activator p25 activates CDK5 in one step by tethering the T-loop in the extended conformation and exposing CDK5's active site for kinase activity. When activated by p25, CDK5 causes the death of neurons, leading to neurodegenerative diseases. Deregulation of CDK5 has been implicated in Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s disease and acute neuronal injury. Regulators of CDK5 activity are considered as potential therapeutic molecules for degenerative diseases. Sometimes, p35, the activator of CDK5, is cleaved in p25 by a protease calcium-dependent, the calpain. This cut form of p35 (p25) is able to activate CDK5 and to trigger a modification of its cellular localization. It can increase its activity too. In Alzheimer’s disease or in the amyotrophic lateral sclerosis, when the ratio of p25 over p35 increases, it leads to hyperactivity of CDK5 which could hyperphosphorylate the protein Tau.<ref name="un" />

==External Resource==
*[http://www.rcsb.org/pdb/explore.do?structureId=1h4l Protein Data Bank file on 1H4L]

==References==
<references />

==Proteopedia Page Contributors and Editors==

Stephanie Müller, Pascaline Menou

Sandbox 210

2011-12-31T17:59:01Z

Pascaline Menou:

===CDK5-p25 complex===

[[Image:1h4l.jpg|left|200px]]
{{STRUCTURE_1h4l| PDB=1h4l | SCENE= }}

== CDK5 – Cyclin dependent Kinase 5 ==

CDK5 is a member of the '''cyclin dependent kinases protein family'''. Cyclin dependent kinases, a large family of serine–threonine kinases, play a crucial role in the regulation of the eukaryotic cell cycle. Since CDK5 plays only little role in cell cycle regulation processes, it is an unusual member of this protein family. Cdk5 gene has been mapped to chromosome seven. The Cdk5 protein is a 33 kDa molecule with kinase activity when bound to its activators. Activated Cdk5 phosphorylates serine and threonine of its substrate that have a proline immediately downstream. This proline is an obligatory requirement while the basic residues, lysine and arginine, are preferred at upstream position +3. Cdk5 phosphorylates serine and threonine of CDK5's substrate in the motif S/TPXK/R where S and T are serine–threonine that can be phosphorylated (X is any amino acid and P is the obligatory proline present at position +1).
CDK5 is rather involved in cell-cell communication, cell morphology and motility, and is indispensable for a correct neural development.<ref name="un">DOI 10.1007/s10571-007-9242-1</ref> CDK5 was identified as member of the CDK-family because of its 58 % sequence homology with mouse CDK1 and its 61 % sequence homology with human CDK2.<ref name="discovery">PMID:1279696</ref> Whereas CDKs are activated upon association with specific cyclins, the kinase activity of CDK5 is activated by its association with non-cyclin molecules such as p25, p35 or p39.<ref>doi:10.1038/371423a0</ref><ref>PMID:7592934</ref>

==History==

Reported by four independent groups of scientists in 1992, CDK5 had multiple names. A first group reported it as a neuronal CDC2 like kinase (NCLK) characterized and cloned from rat brain c-DNA library as a CDK that phosphorylates the lysine–serine–proline motif of neurofilaments. It was reported to have 58% amino acid sequence homology with mouse CDK1 and 61% homology with human CDK2.<ref name="discovery" /> While looking for several CDKs, which play an important role in eukaryotic cell cycle, a second group found CDK5/PSSALARE kinase (with an alpha C helix) among several other CDKs.<ref>PMID: 1639063</ref> A third group of scientists called the same molecule as brain proline-directed protein kinase (BPDK), reporting it in bovine brain with functional similarity to CDC2.<ref>PMID: 1618840</ref> In the same year, the fourth group named it as Tau protein kinase II (TPK II) associated with microtubules.<ref>PMID: 1587865 </ref> Later in 1993, the nomenclature settled down to CDK5 after identifying the 30 kDa protein subunit of the active enzyme.<ref>PMID: 8253190</ref>

==Structure==

Like most eukaryotic protein kinases, Cdk5 has a catalytic domain flanked with additional domains that are involved in its regulation. The catalytic domain has an N-terminal lobe of beta-sheet and alpha-helical C-domain (C lobe) with an ATP binding site between the two. The alpha-helical structure is called PSAALRE based on the polypeptide sequence. A stretch of 20 residues located centrally at the interphase of N and C lobe can acquire a conformation competent for phosphate transfer and is called the activation loop.<ref name="un" />
The subunit of the CDK5 shares also a very similar three-dimensional (3D) structure with CDK2.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>

The activator protein of CDK5, p25, presents a cyclin-box fold domain, which is the structural motif found in the cyclins.
Analyses of the crystal structures of CDK5/p25 show the existence of extensive electrostatic and Van Der Waals interactions between the β sheet, and a small loop following the C helix (f-loop) of CDK5, and an helix of p25.
During the unbinding processes between CDK5 and p25, obvious conformational changes in the C helix and the T loop are observed. The C helix, together with the loop preceding the helix (the p-loop) apparently displaces from its original location towards the p25 side. The distances between the C-alpha carbon atoms of the tip amino acid of the p-loop (Gly43) and the starting amino acid of the C helix (Ser46) before and after pulling are 14.15 Å and 7.23 Å, respectively.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>

===Sequence similarities===
The <scene name='Sandbox_210/1h4l_chainsab/2'>chains A and B</scene> of the CDK5-p25 complex share homologuous sequences with the cell division protein kinase 5 and the <scene name='Sandbox_210/1h4l_chainsde/1'>chains D and E</scene> with the cyclin-dependent kinase 5 activator (p35).

==Biology==

===Physiological Functions of CDK5===

CDK5 is in several aspects important for neuronal development. It is implicated in cytoskeleton assembly and organization during axonal growth, neuronal differentiation and migration, synaptic activities in mature neurons and cell death in neurodegenerative diseases. CDK5 is also involved in the regulation of exocytosis and endocytosis of synaptic vesicles. It modulates signal transduction pathways regulating neuronal survival.<ref>PMID: 11248668</ref> CDK5 is implicated in Alzheimer’s disease as it is involved in the hyperphosphorylation of the protein Tau that leads to neuronal cell death.

===Pathophysiology===

CDK5 is more and more believed to be linked to the etiopathology of neurodegenerative diseases like Alzheimer’s disease or amyotrophic lateral sclerosis (ALS).

===CDK5-p25 complex Control===

The neurotoxic activator p25 activates CDK5 in one step by tethering the T-loop in the extended conformation and exposing CDK5's active site for kinase activity. When activated by p25, CDK5 causes the death of neurons, leading to neurodegenerative diseases. Deregulation of CDK5 has been implicated in Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s disease and acute neuronal injury. Regulators of CDK5 activity are considered as potential therapeutic molecules for degenerative diseases. Sometimes, p35, the activator of CDK5, is cleaved in p25 by a protease calcium-dependent, the calpain. This cut form of p35 (p25) is able to activate CDK5 and to trigger a modification of its cellular localization. It can increase its activity too. In Alzheimer’s disease or in the amyotrophic lateral sclerosis, when the ratio of p25 over p35 increases, it leads to hyperactivity of CDK5 which could hyperphosphorylate the protein Tau.<ref name="un" />

==External Resource==
*[http://www.rcsb.org/pdb/explore.do?structureId=1h4l Protein Data Bank file on 1H4L]

==References==
<references />

==Proteopedia Page Contributors and Editors==

Stephanie Müller, Pascaline Menou

Sandbox 210

2011-12-31T17:54:39Z

Pascaline Menou:

===CDK5-p25 complex===

[[Image:1h4l.jpg|left|200px]]
{{STRUCTURE_1h4l| PDB=1h4l | SCENE= }}

== CDK5 – Cyclin dependent Kinase 5 ==

CDK5 is a member of the '''cyclin dependent kinases protein family'''. Cyclin dependent kinases, a large family of serine–threonine kinases, play a crucial role in the regulation of the eukaryotic cell cycle. Since CDK5 plays only little role in cell cycle regulation processes, it is an unusual member of this protein family. It is rather involved in cell-cell communication, cell morphology and motility, and is indispensable for a correct neural development.<ref name="un">DOI 10.1007/s10571-007-9242-1</ref> CDK5 was identified as member of the CDK-family because of its 58 % sequence homology with mouse CDK1 and its 61 % sequence homology with human CDK2.<ref name="discovery">PMID:1279696</ref> Whereas CDKs are activated upon association with specific cyclins, the kinase activity of CDK5 is activated by its association with non-cyclin molecules such as p25, p35 or p39.<ref>doi:10.1038/371423a0</ref><ref>PMID:7592934</ref>

==History==

Reported by four independent groups of scientists in 1992, CDK5 had multiple names. A first group reported it as a neuronal CDC2 like kinase (NCLK) characterized and cloned from rat brain c-DNA library as a CDK that phosphorylates the lysine–serine–proline motif of neurofilaments. It was reported to have 58% amino acid sequence homology with mouse CDK1 and 61% homology with human CDK2.<ref name="discovery" /> While looking for several CDKs, which play an important role in eukaryotic cell cycle, a second group found CDK5/PSSALARE kinase (with an alpha C helix) among several other CDKs.<ref>PMID: 1639063</ref> A third group of scientists called the same molecule as brain proline-directed protein kinase (BPDK), reporting it in bovine brain with functional similarity to CDC2.<ref>PMID: 1618840</ref> In the same year, the fourth group named it as Tau protein kinase II (TPK II) associated with microtubules.<ref>PMID: 1587865 </ref> Later in 1993, the nomenclature settled down to CDK5 after identifying the 30 kDa protein subunit of the active enzyme.<ref>PMID: 8253190</ref>

==Structure==

Cdk5 gene has been mapped to chromosome seven. The Cdk5 protein is a 33 kDa molecule with kinase activity when bound to its activators. Activated Cdk5 phosphorylates serine and threonine of p25 that have a proline immediately downstream. This proline is an obligatory requirement while the basic residues, lysine and arginine, are preferred at upstream position +3. Cdk5 phosphorylates serine and threonine of p25 in the motif S/TPXK/R where S and T are serine–threonine that can be phosphorylated (X is any amino acid and P is the obligatory proline present at position +1).

Like most eukaryotic protein kinases, Cdk5 has a catalytic domain flanked with additional domains that are involved in its regulation. The catalytic domain has an N-terminal lobe of beta-sheet and alpha-helical C-domain (C lobe) with an ATP binding site between the two. The alpha-helical structure is called PSAALRE based on the polypeptide sequence. A stretch of 20 residues located centrally at the interphase of N and C lobe can acquire a conformation competent for phosphate transfer and is called the activation loop.<ref name="un" />
The subunit of the CDK5 shares also a very similar three-dimensional (3D) structure with CDK2.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>

The activator protein of CDK5, p25, presents a cyclin-box fold domain, which is the structural motif found in the cyclins.
Analyses of the crystal structures of CDK5/p25 show the existence of extensive electrostatic and Van Der Waals interactions between the β sheet, and a small loop following the C helix (f-loop) of CDK5, and an helix of p25.
During the unbinding processes between CDK5 and p25, obvious conformational changes in the C helix and the T loop are observed. The C helix, together with the loop preceding the helix (the p-loop) apparently displaces from its original location towards the p25 side. The distances between the C-alpha carbon atoms of the tip amino acid of the p-loop (Gly43) and the starting amino acid of the C helix (Ser46) before and after pulling are 14.15 Å and 7.23 Å, respectively.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>

===Sequence similarities===
The <scene name='Sandbox_210/1h4l_chainsab/2'>chains A and B</scene> of the CDK5-p25 complex share homologuous sequences with the cell division protein kinase 5 and the <scene name='Sandbox_210/1h4l_chainsde/1'>chains D and E</scene> with the cyclin-dependent kinase 5 activator (p35).

==Biology==

===Physiological Functions of CDK5===

CDK5 is in several aspects important for neuronal development. It is implicated in cytoskeleton assembly and organization during axonal growth, neuronal differentiation and migration, synaptic activities in mature neurons and cell death in neurodegenerative diseases. CDK5 is also involved in the regulation of exocytosis and endocytosis of synaptic vesicles. It modulates signal transduction pathways regulating neuronal survival.<ref>PMID: 11248668</ref> CDK5 is implicated in Alzheimer’s disease as it is involved in the hyperphosphorylation of the protein Tau that leads to neuronal cell death.

===Pathophysiology===

CDK5 is more and more believed to be linked to the etiopathology of neurodegenerative diseases like Alzheimer’s disease or amyotrophic lateral sclerosis (ALS).

===CDK5-p25 complex Control===

The neurotoxic activator p25 activates CDK5 in one step by tethering the T-loop in the extended conformation and exposing CDK5's active site for kinase activity. When activated by p25, CDK5 causes the death of neurons, leading to neurodegenerative diseases. Deregulation of CDK5 has been implicated in Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s disease and acute neuronal injury. Regulators of CDK5 activity are considered as potential therapeutic molecules for degenerative diseases. Sometimes, p35, the activator of CDK5, is cleaved in p25 by a protease calcium-dependent, the calpain. This cut form of p35 (p25) is able to activate CDK5 and to trigger a modification of its cellular localization. It can increase its activity too. In Alzheimer’s disease or in the amyotrophic lateral sclerosis, when the ratio of p25 over p35 increases, it leads to hyperactivity of CDK5 which could hyperphosphorylate the protein Tau.<ref name="un" />

==External Resource==
*[http://www.rcsb.org/pdb/explore.do?structureId=1h4l Protein Data Bank file on 1H4L]

==References==
<references />

==Proteopedia Page Contributors and Editors==

Stephanie Müller, Pascaline Menou

Sandbox 210

2011-12-31T16:41:46Z

Pascaline Menou:

===CDK5-p25 complex===

[[Image:1h4l.jpg|left|200px]]
{{STRUCTURE_1h4l| PDB=1h4l | SCENE= }}

== CDK5 – Cyclin dependent Kinase 5 ==

CDK5 is a member of the '''cyclin dependent kinases protein family'''. Cyclin dependent kinases, a large family of serine–threonine kinases, play a crucial role in the regulation of the eukaryotic cell cycle. Since CDK5 plays only little role in cell cycle regulation processes, it is an unusual member of this protein family. It is rather involved in cell-cell communication, cell morphology and motility, and is indispensable for a correct neural development.<ref name="un">DOI 10.1007/s10571-007-9242-1</ref> CDK5 was identified as member of the CDK-family because of its 58 % sequence homology with mouse CDK1 and its 61 % sequence homology with human CDK2.<ref name="discovery">PMID:1279696</ref> Whereas CDKs are activated upon association with specific cyclins, the kinase activity of CDK5 is activated by its association with non-cyclin molecules such as p25, p35 or p39.<ref>doi:10.1038/371423a0</ref><ref>PMID:7592934</ref>

==History==

Reported by four independent groups of scientists in 1992, CDK5 had multiple names. A first group reported it as a neuronal CDC2 like kinase (NCLK) characterized and cloned from rat brain c-DNA library as a CDK that phosphorylates the lysine–serine–proline motif of neurofilaments. It was reported to have 58% amino acid sequence homology with mouse CDK1 and 61% homology with human CDK2.<ref name="discovery" /> While looking for several CDKs, which play an important role in eukaryotic cell cycle, a second group found CDK5/PSSALARE kinase (with an alpha C helix) among several other CDKs.<ref>PMID: 1639063</ref> A third group of scientists called the same molecule as brain proline-directed protein kinase (BPDK), reporting it in bovine brain with functional similarity to CDC2.<ref>PMID: 1618840</ref> In the same year, the fourth group named it as Tau protein kinase II (TPK II) associated with microtubules.<ref>PMID: 1587865 </ref> Later in 1993, the nomenclature settled down to CDK5 after identifying the 30 kDa protein subunit of the active enzyme.<ref>PMID: 8253190</ref>

==Structure==

Cdk5 gene has been mapped to chromosome seven. The Cdk5 protein is a 33 kDa molecule with kinase activity when bound to its activators. Activated Cdk5 phosphorylates serine and threonine that have a proline immediately downstream. This proline is an obligatory requirement while the basic residues, lysine and arginine, are preferred at upstream position +3. Cdk5 phosphorylates serine and threonine in the motif S/TPXK/R where S and T are serine–threonine that can be phosphorylated (X is any amino acid and P is the obligatory proline present at position +1). Like most eukaryotic protein kinases, Cdk5 has a catalytic domain flanked with additional domains that are involved in its regulation. The catalytic domain has an N-terminal lobe of beta-sheet and alpha-helical C-domain (C lobe) with an ATP binding site between the two. The alpha-helical structure is called PSAALRE based on the polypeptide sequence. A stretch of 20 residues located centrally at the interphase of N and C lobe can acquire a conformation competent for phosphate transfer and is called the activation loop.<ref name="un" />
The subunit of the CDK5 shares also a very similar three-dimensional (3D) structure with CDK2.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>

The activator protein of CDK5, p25, presents a cyclin-box fold domain, which is the structural motif found in the cyclins.
Analyses of the crystal structures of CDK5/p25 show the existence of extensive electrostatic and Van Der Waals interactions between the β sheet, and a small loop following the C helix (f-loop) of CDK5, and an helix of p25.
During the unbinding processes between CDK5 and p25, obvious conformational changes in the C helix and the T loop are observed. The C helix, together with the loop preceding the helix (the p-loop) apparently displaces from its original location towards the p25 side. The distances between the C-alpha carbon atoms of the tip amino acid of the p-loop (Gly43) and the starting amino acid of the C helix (Ser46) before and after pulling are 14.15 Å and 7.23 Å, respectively.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>

===Sequence similarities===
The <scene name='Sandbox_210/1h4l_chainsab/2'>chains A and B</scene> of the CDK5-p25 complex share homologuous sequences with the cell division protein kinase 5 and the <scene name='Sandbox_210/1h4l_chainsde/1'>chains D and E</scene> with the cyclin-dependent kinase 5 activator (p35).

==Biology==

===Physiological Functions of CDK5===

CDK5 is in several aspects important for neuronal development. It is implicated in cytoskeleton assembly and organization during axonal growth, neuronal differentiation and migration, synaptic activities in mature neurons and cell death in neurodegenerative diseases. CDK5 is also involved in the regulation of exocytosis and endocytosis of synaptic vesicles. It modulates signal transduction pathways regulating neuronal survival.<ref>PMID: 11248668</ref> CDK5 is implicated in Alzheimer’s disease as it is involved in the hyperphosphorylation of the protein Tau that leads to neuronal cell death.

===Pathophysiology===

CDK5 is more and more believed to be linked to the etiopathology of neurodegenerative diseases like Alzheimer’s disease or amyotrophic lateral sclerosis (ALS).

===CDK5-p25 complex Control===

The neurotoxic activator p25 activates CDK5 in one step by tethering the T-loop in the extended conformation and exposing CDK5's active site for kinase activity. When activated by p25, CDK5 causes the death of neurons, leading to neurodegenerative diseases. Deregulation of CDK5 has been implicated in Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s disease and acute neuronal injury. Regulators of CDK5 activity are considered as potential therapeutic molecules for degenerative diseases. Sometimes, p35, the activator of CDK5, is cleaved in p25 by a protease calcium-dependent, the calpain. This cut form of p35 (p25) is able to activate CDK5 and to trigger a modification of its cellular localization. It can increase its activity too. In Alzheimer’s disease or in the amyotrophic lateral sclerosis, when the ratio of p25 over p35 increases, it leads to hyperactivity of CDK5 which could hyperphosphorylate the protein Tau.<ref name="un" />

==External Resource==
*[http://www.rcsb.org/pdb/explore.do?structureId=1h4l Protein Data Bank file on 1H4L]

==References==
<references />

==Proteopedia Page Contributors and Editors==

Stephanie Müller, Pascaline Menou

Sandbox 210

2011-12-31T16:40:45Z

Pascaline Menou:

===CDK5-p25 complex===

[[Image:1h4l.jpg|left|200px]]
{{STRUCTURE_1h4l| PDB=1h4l | SCENE= }}

== CDK5 – Cyclin dependent Kinase 5 ==

CDK5 is a member of the '''cyclin dependent kinases protein family'''. Cyclin dependent kinases, a large family of serine–threonine kinases, play a crucial role in the regulation of the eukaryotic cell cycle. Since CDK5 plays only little role in cell cycle regulation processes, it is an unusual member of this protein family. It is rather involved in cell-cell communication, cell morphology and motility, and is indispensable for a correct neural development.<ref name="un">DOI 10.1007/s10571-007-9242-1</ref> CDK5 was identified as member of the CDK-family because of its 58 % sequence homology with mouse CDK1 and its 61 % sequence homology with human CDK2.<ref name="discovery">PMID:1279696</ref> Whereas CDKs are activated upon association with specific cyclins, the kinase activity of CDK5 is activated by its association with non-cyclin molecules such as p25, p35 or p39.<ref>doi:10.1038/371423a0</ref><ref>PMID:7592934</ref>

==History==

Reported by four independent groups of scientists in 1992, CDK5 had multiple names. A first group reported it as a neuronal CDC2 like kinase (NCLK) characterized and cloned from rat brain c-DNA library as a CDK that phosphorylates the lysine–serine–proline motif of neurofilaments. It was reported to have 58% amino acid sequence homology with mouse CDK1 and 61% homology with human CDK2.<ref name="discovery" /> While looking for several CDKs, which play an important role in eukaryotic cell cycle, a second group found CDK5/PSSALARE kinase (with an alpha C helix) among several other CDKs.<ref>PMID: 1639063</ref> A third group of scientists called the same molecule as brain proline-directed protein kinase (BPDK), reporting it in bovine brain with functional similarity to CDC2.<ref>PMID: 1618840</ref> In the same year, the fourth group named it as Tau protein kinase II (TPK II) associated with microtubules.<ref>PMID: 1587865 </ref> Later in 1993, the nomenclature settled down to CDK5 after identifying the 30 kDa protein subunit of the active enzyme.<ref>PMID: 8253190</ref>

==Structure==

Cdk5 gene has been mapped to chromosome seven. The Cdk5 protein is a 33 kDa molecule with kinase activity when bound to its activators. Activated Cdk5 phosphorylates serine and threonine that have a proline immediately downstream. This proline is an obligatory requirement while the basic residues, lysine and arginine, are preferred at upstream position +3. Cdk5 phosphorylates serine and threonine in the motif S/TPXK/R where S and T are serine–threonine that can be phosphorylated (X is any amino acid and P is the obligatory proline present at position +1). Like most eukaryotic protein kinases, Cdk5 has a catalytic domain flanked with additional domains that are involved in its regulation. The catalytic domain has an N-terminal lobe of beta-sheet and alpha-helical C-domain (C lobe) with an ATP binding site between the two. The alpha-helical structure is called PSAALRE based on the polypeptide sequence. A stretch of 20 residues located centrally at the interphase of N and C lobe can acquire a conformation competent for phosphate transfer and is called the activation loop.<ref name="un" />
The subunit of the CDK5 shares also a very similar three-dimensional (3D) structure with CDK2.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>

The activator protein of CDK5, p25, presents a cyclin-box fold domain, which is the structural motif found in the cyclins.
Analyses of the crystal structures of CDK5/p25 show the existence of extensive electrostatic and Van Der Waals interactions between the β sheet, and a small loop following the C helix (f-loop) of CDK5, and an helix of p25.
During the unbinding processes between CDK5 and p25, obvious conformational changes in the C helix and the T loop are observed. The C helix, together with the loop preceding the helix (the p-loop) apparently displaces from its original location towards the p25 side. The distances between the C-alpha carbon atoms of the tip amino acid of the p-loop (Gly43) and the starting amino acid of the C helix (Ser46) before and after pulling are 14.15 Å and 7.23 Å, respectively.<ref>DOI:10.1007/s00894-009-0629-4</ref>

===Sequence similarities===
The <scene name='Sandbox_210/1h4l_chainsab/2'>chains A and B</scene> of the CDK5-p25 complex share homologuous sequences with the cell division protein kinase 5 and the <scene name='Sandbox_210/1h4l_chainsde/1'>chains D and E</scene> with the cyclin-dependent kinase 5 activator (p35).

==Biology==

===Physiological Functions of CDK5===

CDK5 is in several aspects important for neuronal development. It is implicated in cytoskeleton assembly and organization during axonal growth, neuronal differentiation and migration, synaptic activities in mature neurons and cell death in neurodegenerative diseases. CDK5 is also involved in the regulation of exocytosis and endocytosis of synaptic vesicles. It modulates signal transduction pathways regulating neuronal survival.<ref>PMID: 11248668</ref> CDK5 is implicated in Alzheimer’s disease as it is involved in the hyperphosphorylation of the protein Tau that leads to neuronal cell death.

===Pathophysiology===

CDK5 is more and more believed to be linked to the etiopathology of neurodegenerative diseases like Alzheimer’s disease or amyotrophic lateral sclerosis (ALS).

===CDK5-p25 complex Control===

The neurotoxic activator p25 activates CDK5 in one step by tethering the T-loop in the extended conformation and exposing CDK5's active site for kinase activity. When activated by p25, CDK5 causes the death of neurons, leading to neurodegenerative diseases. Deregulation of CDK5 has been implicated in Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s disease and acute neuronal injury. Regulators of CDK5 activity are considered as potential therapeutic molecules for degenerative diseases. Sometimes, p35, the activator of CDK5, is cleaved in p25 by a protease calcium-dependent, the calpain. This cut form of p35 (p25) is able to activate CDK5 and to trigger a modification of its cellular localization. It can increase its activity too. In Alzheimer’s disease or in the amyotrophic lateral sclerosis, when the ratio of p25 over p35 increases, it leads to hyperactivity of CDK5 which could hyperphosphorylate the protein Tau.<ref name="un" />

==External Resource==
*[http://www.rcsb.org/pdb/explore.do?structureId=1h4l Protein Data Bank file on 1H4L]

==References==
<references />

==Proteopedia Page Contributors and Editors==

Stephanie Müller, Pascaline Menou

Sandbox 210

2011-12-31T16:39:15Z

Pascaline Menou:

===CDK5-p25 complex===

[[Image:1h4l.jpg|left|200px]]
{{STRUCTURE_1h4l| PDB=1h4l | SCENE= }}

== CDK5 – Cyclin dependent Kinase 5 ==

CDK5 is a member of the '''cyclin dependent kinases protein family'''. Cyclin dependent kinases, a large family of serine–threonine kinases, play a crucial role in the regulation of the eukaryotic cell cycle. Since CDK5 plays only little role in cell cycle regulation processes, it is an unusual member of this protein family. It is rather involved in cell-cell communication, cell morphology and motility, and is indispensable for a correct neural development.<ref name="un">DOI 10.1007/s10571-007-9242-1</ref> CDK5 was identified as member of the CDK-family because of its 58 % sequence homology with mouse CDK1 and its 61 % sequence homology with human CDK2.<ref name="discovery">PMID:1279696</ref> Whereas CDKs are activated upon association with specific cyclins, the kinase activity of CDK5 is activated by its association with non-cyclin molecules such as p25, p35 or p39.<ref>doi:10.1038/371423a0</ref><ref>PMID:7592934</ref>

==History==

Reported by four independent groups of scientists in 1992, CDK5 had multiple names. A first group reported it as a neuronal CDC2 like kinase (NCLK) characterized and cloned from rat brain c-DNA library as a CDK that phosphorylates the lysine–serine–proline motif of neurofilaments. It was reported to have 58% amino acid sequence homology with mouse CDK1 and 61% homology with human CDK2.<ref name="discovery" /> While looking for several CDKs, which play an important role in eukaryotic cell cycle, a second group found CDK5/PSSALARE kinase (with an alpha C helix) among several other CDKs.<ref>PMID: 1639063</ref> A third group of scientists called the same molecule as brain proline-directed protein kinase (BPDK), reporting it in bovine brain with functional similarity to CDC2.<ref>PMID: 1618840</ref> In the same year, the fourth group named it as Tau protein kinase II (TPK II) associated with microtubules.<ref>PMID: 1587865 </ref> Later in 1993, the nomenclature settled down to CDK5 after identifying the 30 kDa protein subunit of the active enzyme.<ref>PMID: 8253190</ref>

==Structure==

Cdk5 gene has been mapped to chromosome seven. The Cdk5 protein is a 33 kDa molecule with kinase activity when bound to its activators. Activated Cdk5 phosphorylates serine and threonine that have a proline immediately downstream. This proline is an obligatory requirement while the basic residues, lysine and arginine, are preferred at upstream position +3. Cdk5 phosphorylates serine and threonine in the motif S/TPXK/R where S and T are serine–threonine that can be phosphorylated (X is any amino acid and P is the obligatory proline present at position +1). Like most eukaryotic protein kinases, Cdk5 has a catalytic domain flanked with additional domains that are involved in its regulation. The catalytic domain has an N-terminal lobe of beta-sheet and alpha-helical C-domain (C lobe) with an ATP binding site between the two. The alpha-helical structure is called PSAALRE based on the polypeptide sequence. A stretch of 20 residues located centrally at the interphase of N and C lobe can acquire a conformation competent for phosphate transfer and is called the activation loop.<ref>DOI:10.1007/s10571-007-9242-1</ref>
The subunit of the CDK5 shares also a very similar three-dimensional (3D) structure with CDK2.<ref name="premier">doi:10.1007/s00894-009-0629-4</ref>

The activator protein of CDK5, p25, presents a cyclin-box fold domain, which is the structural motif found in the cyclins.
Analyses of the crystal structures of CDK5/p25 show the existence of extensive electrostatic and Van Der Waals interactions between the β sheet, and a small loop following the C helix (f-loop) of CDK5, and an helix of p25.
During the unbinding processes between CDK5 and p25, obvious conformational changes in the C helix and the T loop are observed. The C helix, together with the loop preceding the helix (the p-loop) apparently displaces from its original location towards the p25 side. The distances between the C-alpha carbon atoms of the tip amino acid of the p-loop (Gly43) and the starting amino acid of the C helix (Ser46) before and after pulling are 14.15 Å and 7.23 Å, respectively.<ref>DOI:10.1007/s00894-009-0629-4</ref>

===Sequence similarities===
The <scene name='Sandbox_210/1h4l_chainsab/2'>chains A and B</scene> of the CDK5-p25 complex share homologuous sequences with the cell division protein kinase 5 and the <scene name='Sandbox_210/1h4l_chainsde/1'>chains D and E</scene> with the cyclin-dependent kinase 5 activator (p35).

==Biology==

===Physiological Functions of CDK5===

CDK5 is in several aspects important for neuronal development. It is implicated in cytoskeleton assembly and organization during axonal growth, neuronal differentiation and migration, synaptic activities in mature neurons and cell death in neurodegenerative diseases. CDK5 is also involved in the regulation of exocytosis and endocytosis of synaptic vesicles. It modulates signal transduction pathways regulating neuronal survival.<ref>PMID: 11248668</ref> CDK5 is implicated in Alzheimer’s disease as it is involved in the hyperphosphorylation of the protein Tau that leads to neuronal cell death.

===Pathophysiology===

CDK5 is more and more believed to be linked to the etiopathology of neurodegenerative diseases like Alzheimer’s disease or amyotrophic lateral sclerosis (ALS).

===CDK5-p25 complex Control===

The neurotoxic activator p25 activates CDK5 in one step by tethering the T-loop in the extended conformation and exposing CDK5's active site for kinase activity. When activated by p25, CDK5 causes the death of neurons, leading to neurodegenerative diseases. Deregulation of CDK5 has been implicated in Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease, Huntington’s disease and acute neuronal injury. Regulators of CDK5 activity are considered as potential therapeutic molecules for degenerative diseases. Sometimes, p35, the activator of CDK5, is cleaved in p25 by a protease calcium-dependent, the calpain. This cut form of p35 (p25) is able to activate CDK5 and to trigger a modification of its cellular localization. It can increase its activity too. In Alzheimer’s disease or in the amyotrophic lateral sclerosis, when the ratio of p25 over p35 increases, it leads to hyperactivity of CDK5 which could hyperphosphorylate the protein Tau.<ref name="un" />

==External Resource==
*[http://www.rcsb.org/pdb/explore.do?structureId=1h4l Protein Data Bank file on 1H4L]

==References==
<references />

==Proteopedia Page Contributors and Editors==

Stephanie Müller, Pascaline Menou

Sandbox 210

2011-12-30T16:11:52Z

Pascaline Menou:

Sandbox 210

2011-12-30T16:11:03Z

Pascaline Menou:

Sandbox 210

2011-12-30T16:04:32Z

Pascaline Menou:

Sandbox 210

2011-12-30T15:54:19Z

Pascaline Menou:

Sandbox 210

2011-12-30T15:52:31Z

Pascaline Menou:

Sandbox 210

2011-12-30T15:48:57Z

Pascaline Menou:

Sandbox 210

2011-12-30T15:46:29Z

Pascaline Menou:

Sandbox 210

2011-12-30T15:43:49Z

Pascaline Menou:

Sandbox 210

2011-12-30T15:43:25Z

Pascaline Menou:

Sandbox 210

2011-12-30T15:39:55Z

Pascaline Menou:

Sandbox 210

2011-12-30T15:37:51Z

Pascaline Menou:

Sandbox 210

2011-12-30T15:36:23Z

Pascaline Menou:

Sandbox 210

2011-12-30T15:35:37Z

Pascaline Menou:

Sandbox 210

2011-12-30T15:31:03Z

Pascaline Menou:

Sandbox 210

2011-12-30T15:28:38Z

Pascaline Menou:

Sandbox 210

2011-12-30T15:26:17Z

Pascaline Menou:

Sandbox 210

2011-12-28T14:59:19Z

Pascaline Menou:

Sandbox 210

2011-12-27T14:49:42Z

Pascaline Menou:

Sandbox 210

2011-12-27T14:48:56Z

Pascaline Menou:

Sandbox 210

2011-12-27T14:48:07Z

Pascaline Menou:

Sandbox 210

2011-12-27T14:47:34Z

Pascaline Menou:

Sandbox 210

2011-12-27T14:41:56Z

Pascaline Menou:

Sandbox 210

2011-12-27T14:39:32Z

Pascaline Menou:

Sandbox 210

2011-12-27T14:34:05Z

Pascaline Menou:

Sandbox 210

2011-12-27T14:32:26Z

Pascaline Menou:

Sandbox 210

2011-12-27T14:31:06Z

Pascaline Menou:

Sandbox 210

2011-12-27T14:27:19Z

Pascaline Menou:

Sandbox 210

2011-12-27T14:26:09Z

Pascaline Menou:

Sandbox 210

2011-12-25T11:53:14Z

Pascaline Menou:

Sandbox 210

2011-12-22T18:57:26Z

Pascaline Menou:

Sandbox 210

2011-12-22T18:54:44Z

Pascaline Menou:

Sandbox 210

2011-12-22T18:51:01Z

Pascaline Menou:

Sandbox 210

2011-12-22T18:42:02Z

Pascaline Menou:

Sandbox 210

2011-12-22T18:39:43Z

Pascaline Menou:

Sandbox 210

2011-12-22T18:32:35Z

Pascaline Menou:

Sandbox 210

2011-12-22T18:20:57Z

Pascaline Menou:

Sandbox 210

2011-12-22T18:14:03Z

Pascaline Menou:

Sandbox 210

2011-12-22T18:13:46Z

Pascaline Menou:

Sandbox 210

2011-12-22T18:12:20Z

Pascaline Menou:

Sandbox 210

2011-12-22T18:11:13Z

Pascaline Menou: