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==P-Rex1:Rac1 complex==
==P-Rex1:Rac1 complex==
<StructureSection load='4yon' size='340' side='right' caption='[[4yon]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
<StructureSection load='4yon' size='340' side='right'caption='[[4yon]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4yon]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YON OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YON FirstGlance]. <br>
<table><tr><td colspan='2'>[[4yon]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YON OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YON FirstGlance]. <br>
</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=4yon FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yon OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4yon RCSB], [http://www.ebi.ac.uk/pdbsum/4yon PDBsum]</span></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95&#8491;</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=4yon FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yon OCA], [https://pdbe.org/4yon PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4yon RCSB], [https://www.ebi.ac.uk/pdbsum/4yon PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4yon ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/PREX1_HUMAN PREX1_HUMAN]] Functions as a RAC guanine nucleotide exchange factor (GEF), which activates the Rac proteins by exchanging bound GDP for free GTP. Its activity is synergistically activated by phosphatidylinositol 3,4,5-trisphosphate and the beta gamma subunits of heterotrimeric G protein. May function downstream of heterotrimeric G proteins in neutrophils. [[http://www.uniprot.org/uniprot/RAC1_HUMAN RAC1_HUMAN]] Plasma membrane-associated small GTPase which cycles between active GTP-bound and inactive GDP-bound states. In its active state, binds to a variety of effector proteins to regulate cellular responses such as secretory processes, phagocytosis of apoptotic cells, epithelial cell polarization and growth-factor induced formation of membrane ruffles. Rac1 p21/rho GDI heterodimer is the active component of the cytosolic factor sigma 1, which is involved in stimulation of the NADPH oxidase activity in macrophages (By similarity). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. Stimulates PKN2 kinase activity. In concert with RAB7A, plays a role in regulating the formation of RBs (ruffled borders) in osteoclasts. In glioma cells, promotes cell migration and invasion.<ref>PMID:1643658</ref> <ref>PMID:9121475</ref> <ref>PMID:19934221</ref> <ref>PMID:19403692</ref> <ref>PMID:20696765</ref>  Isoform B has an accelerated GEF-independent GDP/GTP exchange and an impaired GTP hydrolysis, which is restored partially by GTPase-activating proteins. It is able to bind to the GTPase-binding domain of PAK but not full-length PAK in a GTP-dependent manner, suggesting that the insertion does not completely abolish effector interaction.<ref>PMID:1643658</ref> <ref>PMID:9121475</ref> <ref>PMID:19934221</ref> <ref>PMID:19403692</ref> <ref>PMID:20696765</ref>
[https://www.uniprot.org/uniprot/PREX1_HUMAN PREX1_HUMAN] Functions as a RAC guanine nucleotide exchange factor (GEF), which activates the Rac proteins by exchanging bound GDP for free GTP. Its activity is synergistically activated by phosphatidylinositol 3,4,5-trisphosphate and the beta gamma subunits of heterotrimeric G protein. May function downstream of heterotrimeric G proteins in neutrophils.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The P-Rex (phosphatidylinositol(3,4,5)-trisphosphate (PIP3)-dependent Rac exchanger) family (P-Rex1 and P-Rex2) of Rho guanine nucleotide exchange factors (Rho GEFs) activate Rac GTPases to regulate cell migration, invasion and metastasis in several human cancers. The family is unique among Rho GEFs as their activity is regulated by the synergistic binding of PIP3 and Gbetagamma at the plasma membrane. However, the molecular mechanism of this family of multi-domain proteins remains unclear. We report the 1.95 A crystal structure of the catalytic P-Rex1 DH-PH tandem domain in complex with its cognate GTPase, Rac1 (Ras-related C3 botulinum toxin substrate-1). Mutations in the P-Rex1:Rac1 interface reveal a critical role of this complex in signaling downstream of receptor tyrosine kinases and G protein-coupled receptors. Structural data indicate the PIP3/Gbetagamma binding sites are on the opposite surface and markedly removed from the Rac1 interface, supporting a model whereby P-Rex1 binding to PIP3 and/or Gbetagamma releases inhibitory C-terminal domains to expose the Rac1 binding site.
 
The Phosphatidylinositol (3,4,5)-trisphosphate-dependent Rac Exchanger 1:Ras-related C3 Botulinum Toxin Substrate 1 (P-Rex1:Rac1) Complex Reveals the Basis of Rac1 Activation in Breast Cancer Cells.,Lucato CM, Halls ML, Ooms LM, Liu HJ, Mitchell CA, Whisstock JC, Ellisdon AM J Biol Chem. 2015 Jun 24. pii: jbc.M115.660456. PMID:26112412<ref>PMID:26112412</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4yon" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Rac 3D structures|Rac 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Ellisdon, A M]]
[[Category: Homo sapiens]]
[[Category: Lucato, C M]]
[[Category: Large Structures]]
[[Category: Whisstock, J C]]
[[Category: Ellisdon AM]]
[[Category: Protein binding]]
[[Category: Lucato CM]]
[[Category: Whisstock JC]]

Latest revision as of 11:02, 27 September 2023

P-Rex1:Rac1 complexP-Rex1:Rac1 complex

Structural highlights

4yon is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.95Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PREX1_HUMAN Functions as a RAC guanine nucleotide exchange factor (GEF), which activates the Rac proteins by exchanging bound GDP for free GTP. Its activity is synergistically activated by phosphatidylinositol 3,4,5-trisphosphate and the beta gamma subunits of heterotrimeric G protein. May function downstream of heterotrimeric G proteins in neutrophils.

Publication Abstract from PubMed

The P-Rex (phosphatidylinositol(3,4,5)-trisphosphate (PIP3)-dependent Rac exchanger) family (P-Rex1 and P-Rex2) of Rho guanine nucleotide exchange factors (Rho GEFs) activate Rac GTPases to regulate cell migration, invasion and metastasis in several human cancers. The family is unique among Rho GEFs as their activity is regulated by the synergistic binding of PIP3 and Gbetagamma at the plasma membrane. However, the molecular mechanism of this family of multi-domain proteins remains unclear. We report the 1.95 A crystal structure of the catalytic P-Rex1 DH-PH tandem domain in complex with its cognate GTPase, Rac1 (Ras-related C3 botulinum toxin substrate-1). Mutations in the P-Rex1:Rac1 interface reveal a critical role of this complex in signaling downstream of receptor tyrosine kinases and G protein-coupled receptors. Structural data indicate the PIP3/Gbetagamma binding sites are on the opposite surface and markedly removed from the Rac1 interface, supporting a model whereby P-Rex1 binding to PIP3 and/or Gbetagamma releases inhibitory C-terminal domains to expose the Rac1 binding site.

The Phosphatidylinositol (3,4,5)-trisphosphate-dependent Rac Exchanger 1:Ras-related C3 Botulinum Toxin Substrate 1 (P-Rex1:Rac1) Complex Reveals the Basis of Rac1 Activation in Breast Cancer Cells.,Lucato CM, Halls ML, Ooms LM, Liu HJ, Mitchell CA, Whisstock JC, Ellisdon AM J Biol Chem. 2015 Jun 24. pii: jbc.M115.660456. PMID:26112412[1]

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

See Also

References

  1. ↑ Lucato CM, Halls ML, Ooms LM, Liu HJ, Mitchell CA, Whisstock JC, Ellisdon AM. The Phosphatidylinositol (3,4,5)-trisphosphate-dependent Rac Exchanger 1:Ras-related C3 Botulinum Toxin Substrate 1 (P-Rex1:Rac1) Complex Reveals the Basis of Rac1 Activation in Breast Cancer Cells. J Biol Chem. 2015 Jun 24. pii: jbc.M115.660456. PMID:26112412 doi:http://dx.doi.org/10.1074/jbc.M115.660456

4yon, resolution 1.95Å

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