Sandbox Reserved 485: Difference between revisions
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==Structure== | ==Structure== | ||
[[Image:3gj0Ramachandran.jpg|thumb|left|70px|cap=text| Human RanGDP Ramachandran Plot from X-ray Crystallography at 2.3Å]] | [[Image:3gj0Ramachandran.jpg|thumb|left|70px|cap=text| Human RanGDP Ramachandran Plot from X-ray Crystallography at 2.3Å]] | ||
The Ran protein is a small binding protein that consists of 221 residues. The <scene name='Sandbox_Reserved_485/Rangdp_secondary_structure/1'>secondary structure</scene> consists of a mixture of eleven, 70-residue alpha-helices and twelve, 55-residue beta-sheets. The Ran protein is made up of two asymmetric units, Chain A and Chain B. Each unit binds to a Mg2+ and a GDP. Using x-ray crystallography to produce a Ramachandran to determine the Ran structure. The determined crystal structure of the Ran bound GDP and Mg2+ examined at 2.3A resolution showed that the Ran protein shares a high resemblance to the G-domain of the Ras protein. Significant discrepancies were observed however in the GDP and Mg2+ binding sites suggesting that the binding of GTP results in significant conformational changes to the protein. Ran proteins contain a cis-glutamine which is responsible for positioning nucleophilic water which in turns activaes GTPase activity. Along with the consistencies observed in the G-domain, an extended chain and an a-helix were observed on the carboxy terminus while a compliant amino-terminal stretch and an acidic tail were observed on the amino-terminal end. | The Ran protein is a small binding protein that consists of 221 residues. The <scene name='Sandbox_Reserved_485/Rangdp_secondary_structure/1'>secondary structure</scene> consists of a mixture of eleven, 70-residue alpha-helices and twelve, 55-residue beta-sheets. The Ran protein is made up of two asymmetric units, Chain A and Chain B. Each unit binds to a Mg2+ and a GDP. Using x-ray crystallography to produce a Ramachandran to determine the Ran structure. The determined crystal structure of the Ran bound GDP and Mg2+ examined at 2.3A resolution showed that the Ran protein shares a high resemblance to the G-domain of the Ras protein. Significant discrepancies were observed however in the GDP and Mg2+ binding sites suggesting that the binding of GTP results in significant conformational changes to the protein.<ref>http://www.rcsb.org/pdb/explore/explore.do?structureId=3gj0</ref> Ran proteins contain a cis-glutamine which is responsible for positioning nucleophilic water which in turns activaes GTPase activity. Along with the consistencies observed in the G-domain, an extended chain and an a-helix were observed on the carboxy terminus while a compliant amino-terminal stretch and an acidic tail were observed on the amino-terminal end. <ref>http://www.nature.com/emboj/journal/v27/n7/full/emboj200830a.html</ref> | ||
In addition to the Ran protein binding to GTP, Ran also binds to Ran-binding proteins. Ran binding proteins serves as a cofactor in regulating the export and import processes from and to the nucleus and cytoplasm. Ran binding proteins contain a discrete Ran binding domain (RBD) which consists of a single RBD with short extensions at the N and C termini. The RBD is averages 170 residues, 10 charged, hydrophilic residues being highly conserved as they act as binding sites to the contiguous <scene name='Sandbox_Reserved_485/Rangdp_hydrophobic_struct/3'>hydrophobic residues</scene> on the Ran protein. These <scene name='Sandbox_Reserved_485/Rangdp_evo_conserved_struct/1'>highly conserved sequences</scene> [[Image:ZnF-RanGDP.jpg|thumb|70px|cap=text| Zinc Finger bound to RanGDP and Ran's Conformational Changes]]are observed throughout mammalian, yeast and C. elegans. An example of this reaction is Ran interacting with Ran binding proteins that are components of the nuclear pore complex, Nup 153 on the nuclear end and Nup 358 on the cytoplasmic end. Using x-ray crystallography, refined with crystal engineering revealed that these nucleoporins contain distinct Ran-binding zinc finger domains within the switch 1 region that complex with the Ran protein via H-bonds at Lys38 and Thr42. | In addition to the Ran protein binding to GTP, Ran also binds to Ran-binding proteins. Ran binding proteins serves as a cofactor in regulating the export and import processes from and to the nucleus and cytoplasm. Ran binding proteins contain a discrete Ran binding domain (RBD) which consists of a single RBD with short extensions at the N and C termini. The RBD is averages 170 residues, 10 charged, hydrophilic residues being highly conserved as they act as binding sites to the contiguous <scene name='Sandbox_Reserved_485/Rangdp_hydrophobic_struct/3'>hydrophobic residues</scene> on the Ran protein. These <scene name='Sandbox_Reserved_485/Rangdp_evo_conserved_struct/1'>highly conserved sequences</scene> [[Image:ZnF-RanGDP.jpg|thumb|70px|cap=text| Zinc Finger bound to RanGDP and Ran's Conformational Changes]]are observed throughout mammalian, yeast and C. elegans. An example of this reaction is Ran interacting with Ran binding proteins that are components of the nuclear pore complex, Nup 153 on the nuclear end and Nup 358 on the cytoplasmic end. Using x-ray crystallography, refined with crystal engineering revealed that these nucleoporins contain distinct Ran-binding zinc finger domains within the switch 1 region that complex with the Ran protein via H-bonds at Lys38 and Thr42. | ||
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==Possible Applications== | ==Possible Applications== | ||
It is obvious the importance Ran plays within the cell cycle. Defective Ran protein results in irregular reformation of the nuclear envelope, chromosome assembly and microtubule formation. Within the nucleus, malfunctions pertaining to factors associated with specific functions such as splicing and DNA replication These misregulations can result in tissue damage in immunodeficient disorders such as Celiac's disease or X-linked neurodegenerative diseases such as Kennedy's disease. | It is obvious the importance Ran plays within the cell cycle. Defective Ran protein results in irregular reformation of the nuclear envelope, chromosome assembly and microtubule formation. Within the nucleus, malfunctions pertaining to factors associated with specific functions such as splicing and DNA replication These misregulations can result in tissue damage in immunodeficient disorders such as Celiac's disease<ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864807/</ref> or X-linked neurodegenerative diseases such as Kennedy's disease. | ||
Further research is being conducted by Wisconsin Alumni Research Foundation(WARF) to design an inhibitor specific to Ran. Their research hopes to fully understand Ran’s mechanisms and regulatory measures in nuclear transport, mitotic spindle assembly and translational regulation. | Further research is being conducted by Wisconsin Alumni Research Foundation(WARF) to design an inhibitor specific to Ran. Their research hopes to fully understand Ran’s mechanisms and regulatory measures in nuclear transport, mitotic spindle assembly and translational regulation. | ||
==References== | ==References== | ||
<references /> | <references/> | ||
