Sandbox Reserved 485: Difference between revisions

=Ran-GDP (Ras related nuclear protein)=

<Structure load='3gj0' size='275' frame='true' align='right' caption='(PDB:3GJ0) Crystal Structure of Human RanGDP Asymmetric Unit' scene='Insert optional scene name here' />

Ras related nuclear protein, known as the Ran protein, is the most abundant small GTPase in the cell and serves a variety of key roles in cellular regulation and protein transport. Ran is a binding protein that is a subset of the RAS superfamily that actively binds between GDP and GTP to regulate the import and export of RNA molecules and cytoplasmic  material. The Ran protein also plays a key role during interphase and mitosis as the cell progresses through the cell cycle and DNA is synthesized. The majority of the Ran protein is located within the nucleus of eukaryotic cells and interacts with a a variety of proteins due to its diverse uses.<ref>http://www.sciencedirect.com.prox.lib.ncsu.edu/science/article/pii/S0378111911002666</ref>

[[Image:3gj0Ramachandran.jpg|thumb|left|130px|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. X-ray crystallography, examined at 2.3A, produced a Ramachandran plot that determined the crystal structure of Ran bound GDP and Mg2+. The crystal structure showed that the Ran protein shares a high resemblance to the G-domain of the Ras protein. However significant discrepancies were observed 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 turn 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). The Ran binding proteins consists of a single RBD with short extensions at the N and C termini. The RBD averages 170 residues. Ten of these residues are highly conserved as the charged hydrophilic residues 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.<ref>Crystallographic and biochemical analysis of the Ran-binding zinc finger domain.</ref>

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 a wide range of disorders such as infertility, severe 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.