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New page: left|200px<br /> <applet load="1k5d" size="450" color="white" frame="true" align="right" spinBox="true" caption="1k5d, resolution 2.70Å" /> '''Crystal structure o...
 
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[[Image:1k5d.gif|left|200px]]<br />
<applet load="1k5d" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1k5d, resolution 2.70&Aring;" />
'''Crystal structure of Ran-GPPNHP-RanBP1-RanGAP complex'''<br />


==Overview==
==Crystal structure of Ran-GPPNHP-RanBP1-RanGAP complex==
GTPase-activating proteins (GAPs) increase the rate of GTP hydrolysis on, guanine nucleotide-binding proteins by many orders of magnitude. Studies, with Ras and Rho have elucidated the mechanism of GAP action by showing, that their catalytic machinery is both stabilized by GAP binding and, complemented by the insertion of a so-called 'arginine finger' into the, phosphate-binding pocket. This has been proposed as a universal mechanism, for GAP-mediated GTP hydrolysis. Ran is a nuclear Ras-related protein that, regulates both transport between the nucleus and cytoplasm during, interphase, and formation of the mitotic spindle and/or nuclear envelope, in dividing cells. Ran-GTP is hydrolysed by the combined action of, Ran-binding proteins (RanBPs) and RanGAP. Here we present the, three-dimensional structure of a Ran-RanBP1-RanGAP ternary complex in the, ground state and in a transition-state mimic. The structure and, biochemical experiments show that RanGAP does not act through an arginine, finger, that the basic machinery for fast GTP hydrolysis is provided, exclusively by Ran and that correct positioning of the catalytic glutamine, is essential for catalysis.
<StructureSection load='1k5d' size='340' side='right'caption='[[1k5d]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1k5d]] is a 12 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Schizosaccharomyces_pombe Schizosaccharomyces pombe]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1K5D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1K5D FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GNP:PHOSPHOAMINOPHOSPHONIC+ACID-GUANYLATE+ESTER'>GNP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1k5d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1k5d OCA], [https://pdbe.org/1k5d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1k5d RCSB], [https://www.ebi.ac.uk/pdbsum/1k5d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1k5d ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/RAN_HUMAN RAN_HUMAN] GTP-binding protein involved in nucleocytoplasmic transport. Required for the import of protein into the nucleus and also for RNA export. Involved in chromatin condensation and control of cell cycle (By similarity). The complex with BIRC5/ survivin plays a role in mitotic spindle formation by serving as a physical scaffold to help deliver the RAN effector molecule TPX2 to microtubules. Acts as a negative regulator of the kinase activity of VRK1 and VRK2.<ref>PMID:10400640</ref> <ref>PMID:8692944</ref> <ref>PMID:18591255</ref> <ref>PMID:18617507</ref>  Enhances AR-mediated transactivation. Transactivation decreases as the poly-Gln length within AR increases.<ref>PMID:10400640</ref> <ref>PMID:8692944</ref> <ref>PMID:18591255</ref> <ref>PMID:18617507</ref>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/k5/1k5d_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1k5d ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
GTPase-activating proteins (GAPs) increase the rate of GTP hydrolysis on guanine nucleotide-binding proteins by many orders of magnitude. Studies with Ras and Rho have elucidated the mechanism of GAP action by showing that their catalytic machinery is both stabilized by GAP binding and complemented by the insertion of a so-called 'arginine finger' into the phosphate-binding pocket. This has been proposed as a universal mechanism for GAP-mediated GTP hydrolysis. Ran is a nuclear Ras-related protein that regulates both transport between the nucleus and cytoplasm during interphase, and formation of the mitotic spindle and/or nuclear envelope in dividing cells. Ran-GTP is hydrolysed by the combined action of Ran-binding proteins (RanBPs) and RanGAP. Here we present the three-dimensional structure of a Ran-RanBP1-RanGAP ternary complex in the ground state and in a transition-state mimic. The structure and biochemical experiments show that RanGAP does not act through an arginine finger, that the basic machinery for fast GTP hydrolysis is provided exclusively by Ran and that correct positioning of the catalytic glutamine is essential for catalysis.


==Disease==
RanGAP mediates GTP hydrolysis without an arginine finger.,Seewald MJ, Korner C, Wittinghofer A, Vetter IR Nature. 2002 Feb 7;415(6872):662-6. PMID:11832950<ref>PMID:11832950</ref>
Known diseases associated with this structure: Osteolysis, familial expansile OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603499 603499]], Paget disease of bone OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=603499 603499]]


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
1K5D is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Schizosaccharomyces_pombe Schizosaccharomyces pombe] with MG and GNP as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1K5D OCA].
</div>
<div class="pdbe-citations 1k5d" style="background-color:#fffaf0;"></div>


==Reference==
==See Also==
RanGAP mediates GTP hydrolysis without an arginine finger., Seewald MJ, Korner C, Wittinghofer A, Vetter IR, Nature. 2002 Feb 7;415(6872):662-6. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11832950 11832950]
*[[GTP-binding protein 3D structures|GTP-binding protein 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Protein complex]]
[[Category: Large Structures]]
[[Category: Schizosaccharomyces pombe]]
[[Category: Schizosaccharomyces pombe]]
[[Category: Koerner, C.]]
[[Category: Koerner C]]
[[Category: Seewald, M.J.]]
[[Category: Seewald MJ]]
[[Category: Vetter, I.R.]]
[[Category: Vetter IR]]
[[Category: Wittinghofer, A.]]
[[Category: Wittinghofer A]]
[[Category: GNP]]
[[Category: MG]]
[[Category: complex (gtp-binding/gtpase activation)]]
[[Category: gap]]
[[Category: ground state]]
[[Category: gtp hydrolysis]]
[[Category: nuclear transport]]
[[Category: ran]]
[[Category: ranbp1]]
[[Category: rangap]]
[[Category: signal transduction]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 17:47:35 2007''

Latest revision as of 11:52, 16 August 2023

Crystal structure of Ran-GPPNHP-RanBP1-RanGAP complexCrystal structure of Ran-GPPNHP-RanBP1-RanGAP complex

Structural highlights

1k5d is a 12 chain structure with sequence from Homo sapiens and Schizosaccharomyces pombe. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.7Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RAN_HUMAN GTP-binding protein involved in nucleocytoplasmic transport. Required for the import of protein into the nucleus and also for RNA export. Involved in chromatin condensation and control of cell cycle (By similarity). The complex with BIRC5/ survivin plays a role in mitotic spindle formation by serving as a physical scaffold to help deliver the RAN effector molecule TPX2 to microtubules. Acts as a negative regulator of the kinase activity of VRK1 and VRK2.[1] [2] [3] [4] Enhances AR-mediated transactivation. Transactivation decreases as the poly-Gln length within AR increases.[5] [6] [7] [8]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

GTPase-activating proteins (GAPs) increase the rate of GTP hydrolysis on guanine nucleotide-binding proteins by many orders of magnitude. Studies with Ras and Rho have elucidated the mechanism of GAP action by showing that their catalytic machinery is both stabilized by GAP binding and complemented by the insertion of a so-called 'arginine finger' into the phosphate-binding pocket. This has been proposed as a universal mechanism for GAP-mediated GTP hydrolysis. Ran is a nuclear Ras-related protein that regulates both transport between the nucleus and cytoplasm during interphase, and formation of the mitotic spindle and/or nuclear envelope in dividing cells. Ran-GTP is hydrolysed by the combined action of Ran-binding proteins (RanBPs) and RanGAP. Here we present the three-dimensional structure of a Ran-RanBP1-RanGAP ternary complex in the ground state and in a transition-state mimic. The structure and biochemical experiments show that RanGAP does not act through an arginine finger, that the basic machinery for fast GTP hydrolysis is provided exclusively by Ran and that correct positioning of the catalytic glutamine is essential for catalysis.

RanGAP mediates GTP hydrolysis without an arginine finger.,Seewald MJ, Korner C, Wittinghofer A, Vetter IR Nature. 2002 Feb 7;415(6872):662-6. PMID:11832950[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Hsiao PW, Lin DL, Nakao R, Chang C. The linkage of Kennedy's neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator. J Biol Chem. 1999 Jul 16;274(29):20229-34. PMID:10400640
  2. ↑ Moroianu J, Blobel G, Radu A. Nuclear protein import: Ran-GTP dissociates the karyopherin alphabeta heterodimer by displacing alpha from an overlapping binding site on beta. Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7059-62. PMID:8692944
  3. ↑ Xia F, Canovas PM, Guadagno TM, Altieri DC. A survivin-ran complex regulates spindle formation in tumor cells. Mol Cell Biol. 2008 Sep;28(17):5299-311. Epub 2008 Jun 30. PMID:18591255 doi:10.1128/MCB.02039-07
  4. ↑ Sanz-Garcia M, Lopez-Sanchez I, Lazo PA. Proteomics identification of nuclear Ran GTPase as an inhibitor of human VRK1 and VRK2 (vaccinia-related kinase) activities. Mol Cell Proteomics. 2008 Nov;7(11):2199-214. doi: 10.1074/mcp.M700586-MCP200., Epub 2008 Jul 9. PMID:18617507 doi:10.1074/mcp.M700586-MCP200
  5. ↑ Hsiao PW, Lin DL, Nakao R, Chang C. The linkage of Kennedy's neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator. J Biol Chem. 1999 Jul 16;274(29):20229-34. PMID:10400640
  6. ↑ Moroianu J, Blobel G, Radu A. Nuclear protein import: Ran-GTP dissociates the karyopherin alphabeta heterodimer by displacing alpha from an overlapping binding site on beta. Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7059-62. PMID:8692944
  7. ↑ Xia F, Canovas PM, Guadagno TM, Altieri DC. A survivin-ran complex regulates spindle formation in tumor cells. Mol Cell Biol. 2008 Sep;28(17):5299-311. Epub 2008 Jun 30. PMID:18591255 doi:10.1128/MCB.02039-07
  8. ↑ Sanz-Garcia M, Lopez-Sanchez I, Lazo PA. Proteomics identification of nuclear Ran GTPase as an inhibitor of human VRK1 and VRK2 (vaccinia-related kinase) activities. Mol Cell Proteomics. 2008 Nov;7(11):2199-214. doi: 10.1074/mcp.M700586-MCP200., Epub 2008 Jul 9. PMID:18617507 doi:10.1074/mcp.M700586-MCP200
  9. ↑ Seewald MJ, Korner C, Wittinghofer A, Vetter IR. RanGAP mediates GTP hydrolysis without an arginine finger. Nature. 2002 Feb 7;415(6872):662-6. PMID:11832950 doi:10.1038/415662a

1k5d, resolution 2.70Å

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