User:Olivier Laprevote/Sandbox 1

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== Function ==
== Function ==
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Vav1 is a '''Guanine Exchange Factor''' (GEF) for the Rho/Rac protein family <ref> http://mcb.asm.org/content/20/5/1461.full </ref>.
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Guanine nucleotide exchange factor ('''GEF''') of the Rho/Rac GTPases <ref>http://www.uniprot.org/uniprot/P15498#function</ref>, including Ras and Cdc42.
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It is involved in cellular response to external stimuli, by inducing cytoskeletal rearrangement or by inter-mediating pathways cascades. As such, the '''proto-oncogene''' encoded Vav1 protein has a role in growth and division of the cell, but also in apoptotic pathways.
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<scene name='75/751211/Vav_ras/1'>Vav interacting with Ras</scene>
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Vav1 is mainly found in hematopoietic cells <ref> http://www.proteinatlas.org/ENSG00000141968-VAV1/tissue </ref> and is involved in the '''differentiation''' of T lymphocytes, then in B and T cells '''development''' and '''maturation''' <ref> PMID:14623913 </ref>.
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Vav1 also has a role in Ca2+ induced signalling pathways in immune response of B and T cells.
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HIV-1 Nef protein has been found to bind specifically to Vav1, affecting its nucleus-to-cytoplasm distribution, and thus delaying the immune reaction <ref> PMID:14597672 </ref>
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== Disease ==
== Disease ==
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<scene name='75/751211/Ac_domain/1'>Acidic (Ac) domain</scene> (residues 134 - 187): contains the Tyrosine (Y174) which '''activates Vav''' when phosphorylated. <ref>PMID:20141838 </ref>
<scene name='75/751211/Ac_domain/1'>Acidic (Ac) domain</scene> (residues 134 - 187): contains the Tyrosine (Y174) which '''activates Vav''' when phosphorylated. <ref>PMID:20141838 </ref>
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<scene name='75/751211/Dh_domain/1'>DBL-homology (DH) domain</scene> (residues 194 - 373): present in every Rho/rac GEF, it is the '''active site''' of the GTP exchange with the C1 domain in Vav. It always has a PH domain just after its C terminal.<ref>http://pfam.xfam.org/family/PF00621</ref>
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<scene name='75/751211/Dh_domain/1'>DBL-homology (DH) domain</scene> (residues 194 - 373): present in every Rho/rac GEF, it is the '''active site''' of the GTP exchange with the C1 domain in Vav and it promotes the '''binding to rho GTPase''' with the help of the C1 domain. It always has a PH domain just after its C terminal.<ref>http://pfam.xfam.org/family/PF00621</ref>
<scene name='75/751211/Ph_domain/1'>Pleckstrin-homology (PH) domain</scene> (residues 402 - 504): point mutation in it don't change the exchange activity of Vav, so it '''isn't directly involved''' in its GEF function <ref>PMID: 10523675 </ref>. But the presence of '''phosphatidylinositol-4,5-bisphosphate''' (PIP 2) inhibits 90% of Vav activity while '''phosphatidylinositol-3,4,5-trisphosphate''' doubles it. It is very likely that the interactions between these lipids and Vav happen on the PH domain, as it is commonly the case on other proteins with this region. It should be noted that the activation of Vav is made in parallel of the one of '''PI3-kinase''' in TCR and BCR pathway. <ref>PMID: 9438848</ref>
<scene name='75/751211/Ph_domain/1'>Pleckstrin-homology (PH) domain</scene> (residues 402 - 504): point mutation in it don't change the exchange activity of Vav, so it '''isn't directly involved''' in its GEF function <ref>PMID: 10523675 </ref>. But the presence of '''phosphatidylinositol-4,5-bisphosphate''' (PIP 2) inhibits 90% of Vav activity while '''phosphatidylinositol-3,4,5-trisphosphate''' doubles it. It is very likely that the interactions between these lipids and Vav happen on the PH domain, as it is commonly the case on other proteins with this region. It should be noted that the activation of Vav is made in parallel of the one of '''PI3-kinase''' in TCR and BCR pathway. <ref>PMID: 9438848</ref>
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phorbol esters/diacylglycerol binding (C1) domain :
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<scene name='75/751211/C1_domain/1'>Phorbol esters/diacylglycerol binding (C1) domain</scene> (508 - 584) : has a cooperative action with the DH domain to '''bind to the rho GTPase''' and to '''promote the GEF activity''' of Vav.

Revision as of 13:57, 27 January 2017

Proto-oncogene vav

Caption for this structure

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References

  1. ↑ Hanson, R. M., Prilusky, J., Renjian, Z., Nakane, T. and Sussman, J. L. (2013), JSmol and the Next-Generation Web-Based Representation of 3D Molecular Structure as Applied to Proteopedia. Isr. J. Chem., 53:207-216. doi:http://dx.doi.org/10.1002/ijch.201300024
  2. ↑ Herraez A. Biomolecules in the computer: Jmol to the rescue. Biochem Mol Biol Educ. 2006 Jul;34(4):255-61. doi: 10.1002/bmb.2006.494034042644. PMID:21638687 doi:10.1002/bmb.2006.494034042644
  3. ↑ http://www.uniprot.org/uniprot/P15498#function
  4. ↑ http://smart.embl.de/smart/show_motifs.pl?GENOMIC=1&DO_PFAM=DO_PFAM&INCLUDE_SIGNALP=INCLUDE_SIGNALP&ID=9606.ENSP00000472929
  5. ↑ Yu B, Martins IR, Li P, Amarasinghe GK, Umetani J, Fernandez-Zapico ME, Billadeau DD, Machius M, Tomchick DR, Rosen MK. Structural and energetic mechanisms of cooperative autoinhibition and activation of Vav1. Cell. 2010 Jan 22;140(2):246-56. PMID:20141838 doi:10.1016/j.cell.2009.12.033
  6. ↑ Llorca O, Arias-Palomo E, Zugaza JL, Bustelo XR. Global conformational rearrangements during the activation of the GDP/GTP exchange factor Vav3. EMBO J. 2005 Apr 6;24(7):1330-40. Epub 2005 Mar 10. PMID:15775967 doi:http://dx.doi.org/10.1038/sj.emboj.7600617
  7. ↑ Yu B, Martins IR, Li P, Amarasinghe GK, Umetani J, Fernandez-Zapico ME, Billadeau DD, Machius M, Tomchick DR, Rosen MK. Structural and energetic mechanisms of cooperative autoinhibition and activation of Vav1. Cell. 2010 Jan 22;140(2):246-56. PMID:20141838 doi:10.1016/j.cell.2009.12.033
  8. ↑ http://pfam.xfam.org/family/PF00621
  9. ↑ Movilla N, Bustelo XR. Biological and regulatory properties of Vav-3, a new member of the Vav family of oncoproteins. Mol Cell Biol. 1999 Nov;19(11):7870-85. PMID:10523675
  10. ↑ Han J, Luby-Phelps K, Das B, Shu X, Xia Y, Mosteller RD, Krishna UM, Falck JR, White MA, Broek D. Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav. Science. 1998 Jan 23;279(5350):558-60. PMID:9438848

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Olivier Laprevote

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