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3zdt

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Revision as of 11:50, 4 August 2016

Crystal structure of basic patch mutant FAK FERM domain FAK31- 405 K216A, K218A, R221A, K222A

Structural highlights

3zdt is a 2 chain structure with sequence from Chick. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Activity:	Non-specific protein-tyrosine kinase, with EC number 2.7.10.2
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[FAK1_CHICK] Non-receptor protein-tyrosine kinase that plays an essential role in regulating cell migration, adhesion, spreading, reorganization of the actin cytoskeleton, formation and disassembly of focal adhesions and cell protrusions, cell cycle progression, cell proliferation and apoptosis. Required for early embryonic development, embryonic angiogenesis, normal cardiomyocyte migration and proliferation, and normal heart development. Regulates axon growth and neuronal cell migration, axon branching and synapse formation; required for normal development of the nervous system. Plays a role in osteogenesis and differentiation of osteoblasts. Functions in integrin signal transduction, but also in signaling downstream of numerous growth factor receptors, G-protein coupled receptors (GPCR), ephrin receptors, netrin receptors and LDL receptors. Forms multisubunit signaling complexes with SRC and SRC family members upon activation; this leads to the phosphorylation of additional tyrosine residues, creating binding sites for scaffold proteins, effectors and substrates. Regulates numerous signaling pathways. Promotes activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascade. Promotes activation of MAPK1/ERK2, MAPK3/ERK1 and the MAP kinase signaling cascade. Promotes localized and transient activation of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), and thereby modulates the activity of Rho family GTPases. Signaling via CAS family members mediates activation of RAC1. Regulates P53/TP53 activity and stability. Phosphorylates SRC; this increases SRC kinase activity. Isoform 2 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase (NRTK) with key roles in integrating growth and cell matrix adhesion signals, and FAK is a major driver of invasion and metastasis in cancer. Cell adhesion via integrin receptors is well known to trigger FAK signaling, and many of the players involved are known; however, mechanistically, FAK activation is not understood. Here, using a multidisciplinary approach, including biochemical, biophysical, structural, computational, and cell biology approaches, we provide a detailed view of a multistep activation mechanism of FAK initiated by phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. Interestingly, the mechanism differs from canonical NRTK activation and is tailored to the dual catalytic and scaffolding function of FAK. We find PI(4,5)P2 induces clustering of FAK on the lipid bilayer by binding a basic region in the regulatory 4.1, ezrin, radixin, moesin homology (FERM) domain. In these clusters, PI(4,5)P2 induces a partially open FAK conformation where the autophosphorylation site is exposed, facilitating efficient autophosphorylation and subsequent Src recruitment. However, PI(4,5)P2 does not release autoinhibitory interactions; rather, Src phosphorylation of the activation loop in FAK results in release of the FERM/kinase tether and full catalytic activation. We propose that PI(4,5)P2 and its generation in focal adhesions by the enzyme phosphatidylinositol 4-phosphate 5-kinase type Igamma are important in linking integrin signaling to FAK activation.

Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes.,Goni GM, Epifano C, Boskovic J, Camacho-Artacho M, Zhou J, Bronowska A, Martin MT, Eck MJ, Kremer L, Grater F, Gervasio FL, Perez-Moreno M, Lietha D Proc Natl Acad Sci U S A. 2014 Jul 21. pii: 201317022. PMID:25049397^[7]

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

References

↑ Ren XR, Ming GL, Xie Y, Hong Y, Sun DM, Zhao ZQ, Feng Z, Wang Q, Shim S, Chen ZF, Song HJ, Mei L, Xiong WC. Focal adhesion kinase in netrin-1 signaling. Nat Neurosci. 2004 Nov;7(11):1204-12. Epub 2004 Oct 17. PMID:15494733 doi:10.1038/nn1330
↑ Li W, Lee J, Vikis HG, Lee SH, Liu G, Aurandt J, Shen TL, Fearon ER, Guan JL, Han M, Rao Y, Hong K, Guan KL. Activation of FAK and Src are receptor-proximal events required for netrin signaling. Nat Neurosci. 2004 Nov;7(11):1213-21. Epub 2004 Oct 17. PMID:15494734 doi:10.1038/nn1329
↑ Liu G, Beggs H, Jurgensen C, Park HT, Tang H, Gorski J, Jones KR, Reichardt LF, Wu J, Rao Y. Netrin requires focal adhesion kinase and Src family kinases for axon outgrowth and attraction. Nat Neurosci. 2004 Nov;7(11):1222-32. Epub 2004 Oct 17. PMID:15494732 doi:10.1038/nn1331
↑ Koshman YE, Kim T, Chu M, Engman SJ, Iyengar R, Robia SL, Samarel AM. FRNK inhibition of focal adhesion kinase-dependent signaling and migration in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2010 Nov;30(11):2226-33. doi:, 10.1161/ATVBAHA.110.212761. Epub 2010 Aug 12. PMID:20705914 doi:10.1161/ATVBAHA.110.212761
↑ Koshman YE, Chu M, Engman SJ, Kim T, Iyengar R, Robia SL, Samarel AM. Focal adhesion kinase-related nonkinase inhibits vascular smooth muscle cell invasion by focal adhesion targeting, tyrosine 168 phosphorylation, and competition for p130(Cas) binding. Arterioscler Thromb Vasc Biol. 2011 Nov;31(11):2432-40. doi:, 10.1161/ATVBAHA.111.235549. PMID:21852560 doi:10.1161/ATVBAHA.111.235549
↑ Chu M, Iyengar R, Koshman YE, Kim T, Russell B, Martin JL, Heroux AL, Robia SL, Samarel AM. Serine-910 phosphorylation of focal adhesion kinase is critical for sarcomere reorganization in cardiomyocyte hypertrophy. Cardiovasc Res. 2011 Dec 1;92(3):409-19. doi: 10.1093/cvr/cvr247. Epub 2011 Sep, 21. PMID:21937583 doi:10.1093/cvr/cvr247
↑ Goni GM, Epifano C, Boskovic J, Camacho-Artacho M, Zhou J, Bronowska A, Martin MT, Eck MJ, Kremer L, Grater F, Gervasio FL, Perez-Moreno M, Lietha D. Phosphatidylinositol 4,5-bisphosphate triggers activation of focal adhesion kinase by inducing clustering and conformational changes. Proc Natl Acad Sci U S A. 2014 Jul 21. pii: 201317022. PMID:25049397 doi:http://dx.doi.org/10.1073/pnas.1317022111

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3zdt"

@@ Line 1: / Line 1: @@
 ==Crystal structure of basic patch mutant FAK FERM domain FAK31- 405 K216A, K218A, R221A, K222A==
 <StructureSection load='3zdt' size='340' side='right' caption='[[3zdt]], [[Resolution|resolution]] 3.15&Aring;' scene=''>
@@ Line 4: / Line 5: @@
 <table><tr><td colspan='2'>[[3zdt]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Chick Chick]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZDT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZDT FirstGlance]. <br>
 </td></tr><tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></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=3zdt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zdt OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3zdt RCSB], [http://www.ebi.ac.uk/pdbsum/3zdt PDBsum]</span></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=3zdt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zdt OCA], [http://pdbe.org/3zdt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3zdt RCSB], [http://www.ebi.ac.uk/pdbsum/3zdt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3zdt ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 16: / Line 17: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3zdt" style="background-color:#fffaf0;"></div>
 ==See Also==

3zdt

From Proteopedia

Revision as of 11:50, 4 August 2016

Crystal structure of basic patch mutant FAK FERM domain FAK31- 405 K216A, K218A, R221A, K222A

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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