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4d4r

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Revision as of 02:40, 11 December 2016

Focal Adhesion Kinase catalytic domain

Structural highlights

4d4r is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	4d4s, 4d4v, 4d4y, 4d55, 4d58, 4d5h, 4d5k
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 that regulates cell signaling, proliferation, migration, and development. A major mechanism of regulation of FAK activity is an intramolecular autoinhibitory interaction between two of its domains-the catalytic and FERM domains. Upon cell adhesion to the extracellular matrix, FAK is being translocated toward focal adhesion sites and activated. Interactions of FAK with phosphoinositide phosphatidylinsositol-4,5-bis-phosphate (PIP2) are required to activate FAK. However, the molecular mechanism of the activation remains poorly understood. Recent fluorescence resonance energy transfer experiments revealed a closure of the FERM-kinase interface upon ATP binding, which is reversed upon additional binding of PIP2. Here, we addressed the allosteric regulation of FAK by performing all-atom molecular-dynamics simulations of a FAK fragment containing the catalytic and FERM domains, and comparing the dynamics in the absence or presence of ATP and PIP2. As a major conformational change, we observe a closing and opening motion upon ATP and additional PIP2 binding, respectively, in good agreement with the fluorescence resonance energy transfer experiments. To reveal how the binding of the regulatory PIP2 to the FERM F2 lobe is transduced to the very distant F1/N-lobe interface, we employed force distribution analysis. We identified a network of mainly charged residue-residue interactions spanning from the PIP2 binding site to the distant interface between the kinase and FERM domains, comprising candidate residues for mutagenesis to validate the predicted mechanism of FAK activation.

Allosteric Regulation of Focal Adhesion Kinase by PIP2 and ATP.,Zhou J, Bronowska A, Le Coq J, Lietha D, Grater F Biophys J. 2015 Feb 3;108(3):698-705. doi: 10.1016/j.bpj.2014.11.3454. PMID:25650936^[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
↑ Zhou J, Bronowska A, Le Coq J, Lietha D, Grater F. Allosteric Regulation of Focal Adhesion Kinase by PIP2 and ATP. Biophys J. 2015 Feb 3;108(3):698-705. doi: 10.1016/j.bpj.2014.11.3454. PMID:25650936 doi:http://dx.doi.org/10.1016/j.bpj.2014.11.3454

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/4d4r"

@@ Line 1: / Line 1: @@
 ==Focal Adhesion Kinase catalytic domain==
 <StructureSection load='4d4r' size='340' side='right' caption='[[4d4r]], [[Resolution|resolution]] 1.55&Aring;' scene=''>
@@ Line 6: / Line 7: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4d4s|4d4s]], [[4d4v|4d4v]], [[4d4y|4d4y]], [[4d55|4d55]], [[4d58|4d58]], [[4d5h|4d5h]], [[4d5k|4d5k]]</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=4d4r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d4r OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4d4r RCSB], [http://www.ebi.ac.uk/pdbsum/4d4r 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=4d4r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4d4r OCA], [http://pdbe.org/4d4r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4d4r RCSB], [http://www.ebi.ac.uk/pdbsum/4d4r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4d4r ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4d4r" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Focal adhesion kinase|Focal adhesion kinase]]
 == References ==
 <references/>

4d4r

From Proteopedia

Revision as of 02:40, 11 December 2016

Focal Adhesion Kinase catalytic domain

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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