5cll: Difference between revisions

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'''Unreleased structure'''
==Truncated Ran wild type in complex with GDP-BeF and RanBD1==
<StructureSection load='5cll' size='340' side='right' caption='[[5cll]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5cll]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CLL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CLL FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BEF:BERYLLIUM+TRIFLUORIDE+ION'>BEF</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5cll FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cll OCA], [http://www.rcsb.org/pdb/explore.do?structureId=5cll RCSB], [http://www.ebi.ac.uk/pdbsum/5cll PDBsum]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/RBP2_HUMAN RBP2_HUMAN]] Defects in RANBP2 are the cause of encephalopathy acute infection-induced type 3 (IIAE3) [MIM:[http://omim.org/entry/608033 608033]]. A rapidly progressive encephalopathy manifesting in susceptibile individuals with seizures and coma. It can occur within days in otherwise healthy children after common viral infections such as influenza and parainfluenza, without evidence of viral infection of the brain or inflammatory cell infiltration. Brain T2-weighted magnetic resonance imaging reveals characteristic symmetric lesions present in the thalami, pons and brainstem. Note=Mutations in the RANBP2 gene predispose to IIAE3, but by themselves are insufficient to make the phenotype fully penetrant; additional genetic and environmental factors are required (PubMed:19118815).<ref>PMID:19118815</ref> 
== Function ==
[[http://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>  [[http://www.uniprot.org/uniprot/RBP2_HUMAN RBP2_HUMAN]] E3 SUMO-protein ligase which facilitates SUMO1 and SUMO2 conjugation by UBE2I. Involved in transport factor (Ran-GTP, karyopherin)-mediated protein import via the F-G repeat-containing domain which acts as a docking site for substrates. Could also have isomerase or chaperone activity and may bind RNA or DNA. Component of the nuclear export pathway. Specific docking site for the nuclear export factor exportin-1.<ref>PMID:11792325</ref> <ref>PMID:12032081</ref> <ref>PMID:15378033</ref> <ref>PMID:15931224</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Small GTPases regulate key processes in cells. Malfunction of their GTPase reaction by mutations is involved in severe diseases. Here, we compare the GTPase reaction of the slower hydrolyzing GTPase Ran with Ras. By combination of time-resolved FTIR-difference spectroscopy and QM/MM simulations we elucidate that the Mg2+ coordination by the phosphate groups, which varies largely among the X-ray structures, is the same for Ran and Ras. A new X-ray structure of a Ran.RanBD1 complex with improved resolution confirmed this finding and revealed a general problem with the refinement of Mg2+ in GTPases. The Mg2+ coordination is not responsible for the much slower GTPase reaction of Ran. Instead, the location of the Tyr39 side chain of Ran between the gamma-phosphate and Gln69 prevents the optimal positioning of the attacking water molecule by the Gln69 relative to the gamma-phosphate. This is confirmed in the RanY39A.RanBD1 crystal structure. The QM/MM simulations provide IR spectra of the catalytic center which agree very nicely with the experimental ones. The combination of both methods can correlate spectra with structure at atomic detail. For example the FTIR difference spectra of RasA18T and RanT25A mutants show that spectral differences are mainly due to the hydrogen bond of Thr25 to the alpha-phosphate in Ran. By integration of X-ray structure analysis, experimental and theoretical IR spectroscopy the catalytic center of the X-ray structural models are further refined to sub-Angstrom resolution, allowing an improved understanding of catalysis.


The entry 5cll is ON HOLD
Catalysis of GTP hydrolysis by small GTPases at atomic detail by integration of X-ray crystallography, experimental and theoretical IR spectroscopy.,Rudack T, Jenrich S, Brucker S, Vetter IR, Gerwert K, Kotting C J Biol Chem. 2015 Aug 13. pii: jbc.M115.648071. PMID:26272610<ref>PMID:26272610</ref>


Authors: Vetter, I.R., Brucker, S.
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
</div>
Description: Truncated Ran wild type in complex with GDP-BeF and RanBD1
== References ==
[[Category: Unreleased Structures]]
<references/>
__TOC__
</StructureSection>
[[Category: Brucker, S]]
[[Category: Brucker, S]]
[[Category: Vetter, I.R]]
[[Category: Vetter, I R]]
[[Category: Gtpase]]
[[Category: Hydrolase]]
[[Category: Nuclear transport]]
[[Category: Ran binding protein]]

Revision as of 14:16, 9 September 2015

Truncated Ran wild type in complex with GDP-BeF and RanBD1Truncated Ran wild type in complex with GDP-BeF and RanBD1

Structural highlights

5cll is a 4 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, ,
Resources:FirstGlance, OCA, RCSB, PDBsum

Disease

[RBP2_HUMAN] Defects in RANBP2 are the cause of encephalopathy acute infection-induced type 3 (IIAE3) [MIM:608033]. A rapidly progressive encephalopathy manifesting in susceptibile individuals with seizures and coma. It can occur within days in otherwise healthy children after common viral infections such as influenza and parainfluenza, without evidence of viral infection of the brain or inflammatory cell infiltration. Brain T2-weighted magnetic resonance imaging reveals characteristic symmetric lesions present in the thalami, pons and brainstem. Note=Mutations in the RANBP2 gene predispose to IIAE3, but by themselves are insufficient to make the phenotype fully penetrant; additional genetic and environmental factors are required (PubMed:19118815).[1]

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.[2] [3] [4] [5] Enhances AR-mediated transactivation. Transactivation decreases as the poly-Gln length within AR increases.[6] [7] [8] [9] [RBP2_HUMAN] E3 SUMO-protein ligase which facilitates SUMO1 and SUMO2 conjugation by UBE2I. Involved in transport factor (Ran-GTP, karyopherin)-mediated protein import via the F-G repeat-containing domain which acts as a docking site for substrates. Could also have isomerase or chaperone activity and may bind RNA or DNA. Component of the nuclear export pathway. Specific docking site for the nuclear export factor exportin-1.[10] [11] [12] [13]

Publication Abstract from PubMed

Small GTPases regulate key processes in cells. Malfunction of their GTPase reaction by mutations is involved in severe diseases. Here, we compare the GTPase reaction of the slower hydrolyzing GTPase Ran with Ras. By combination of time-resolved FTIR-difference spectroscopy and QM/MM simulations we elucidate that the Mg2+ coordination by the phosphate groups, which varies largely among the X-ray structures, is the same for Ran and Ras. A new X-ray structure of a Ran.RanBD1 complex with improved resolution confirmed this finding and revealed a general problem with the refinement of Mg2+ in GTPases. The Mg2+ coordination is not responsible for the much slower GTPase reaction of Ran. Instead, the location of the Tyr39 side chain of Ran between the gamma-phosphate and Gln69 prevents the optimal positioning of the attacking water molecule by the Gln69 relative to the gamma-phosphate. This is confirmed in the RanY39A.RanBD1 crystal structure. The QM/MM simulations provide IR spectra of the catalytic center which agree very nicely with the experimental ones. The combination of both methods can correlate spectra with structure at atomic detail. For example the FTIR difference spectra of RasA18T and RanT25A mutants show that spectral differences are mainly due to the hydrogen bond of Thr25 to the alpha-phosphate in Ran. By integration of X-ray structure analysis, experimental and theoretical IR spectroscopy the catalytic center of the X-ray structural models are further refined to sub-Angstrom resolution, allowing an improved understanding of catalysis.

Catalysis of GTP hydrolysis by small GTPases at atomic detail by integration of X-ray crystallography, experimental and theoretical IR spectroscopy.,Rudack T, Jenrich S, Brucker S, Vetter IR, Gerwert K, Kotting C J Biol Chem. 2015 Aug 13. pii: jbc.M115.648071. PMID:26272610[14]

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

References

  1. ↑ Neilson DE, Adams MD, Orr CM, Schelling DK, Eiben RM, Kerr DS, Anderson J, Bassuk AG, Bye AM, Childs AM, Clarke A, Crow YJ, Di Rocco M, Dohna-Schwake C, Dueckers G, Fasano AE, Gika AD, Gionnis D, Gorman MP, Grattan-Smith PJ, Hackenberg A, Kuster A, Lentschig MG, Lopez-Laso E, Marco EJ, Mastroyianni S, Perrier J, Schmitt-Mechelke T, Servidei S, Skardoutsou A, Uldall P, van der Knaap MS, Goglin KC, Tefft DL, Aubin C, de Jager P, Hafler D, Warman ML. Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2. Am J Hum Genet. 2009 Jan;84(1):44-51. doi: 10.1016/j.ajhg.2008.12.009. PMID:19118815 doi:10.1016/j.ajhg.2008.12.009
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ Pichler A, Gast A, Seeler JS, Dejean A, Melchior F. The nucleoporin RanBP2 has SUMO1 E3 ligase activity. Cell. 2002 Jan 11;108(1):109-20. PMID:11792325
  11. ↑ Kirsh O, Seeler JS, Pichler A, Gast A, Muller S, Miska E, Mathieu M, Harel-Bellan A, Kouzarides T, Melchior F, Dejean A. The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase. EMBO J. 2002 Jun 3;21(11):2682-91. PMID:12032081 doi:10.1093/emboj/21.11.2682
  12. ↑ Pichler A, Knipscheer P, Saitoh H, Sixma TK, Melchior F. The RanBP2 SUMO E3 ligase is neither HECT- nor RING-type. Nat Struct Mol Biol. 2004 Oct;11(10):984-91. Epub 2004 Sep 19. PMID:15378033 doi:10.1038/nsmb834
  13. ↑ Reverter D, Lima CD. Insights into E3 ligase activity revealed by a SUMO-RanGAP1-Ubc9-Nup358 complex. Nature. 2005 Jun 2;435(7042):687-92. PMID:15931224 doi:10.1038/nature03588
  14. ↑ Rudack T, Jenrich S, Brucker S, Vetter IR, Gerwert K, Kotting C. Catalysis of GTP hydrolysis by small GTPases at atomic detail by integration of X-ray crystallography, experimental and theoretical IR spectroscopy. J Biol Chem. 2015 Aug 13. pii: jbc.M115.648071. PMID:26272610 doi:http://dx.doi.org/10.1074/jbc.M115.648071

5cll, resolution 2.45Å

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