View source for 3zdt


==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=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3zdt]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Gallus_gallus Gallus gallus]. 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 [https://proteopedia.org/fgij/fg.htm?mol=3ZDT FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.15&#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=3zdt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zdt OCA], [https://pdbe.org/3zdt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3zdt RCSB], [https://www.ebi.ac.uk/pdbsum/3zdt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3zdt ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/FAK1_CHICK 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.<ref>PMID:15494733</ref> <ref>PMID:15494734</ref> <ref>PMID:15494732</ref> <ref>PMID:20705914</ref> <ref>PMID:21852560</ref> <ref>PMID:21937583</ref> 
<div style="background-color:#fffaf0;">
== 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<ref>PMID:25049397</ref>

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==
*[[Focal adhesion kinase 3D structures|Focal adhesion kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Gallus gallus]]
[[Category: Large Structures]]
[[Category: Boskovic J]]
[[Category: Camacho-Artacho M]]
[[Category: Eck MJ]]
[[Category: Epifano C]]
[[Category: Gervasio FL]]
[[Category: Goni GM]]
[[Category: Graeter F]]
[[Category: Kremer L]]
[[Category: Lietha D]]
[[Category: Martin MT]]
[[Category: Perez-Moreno M]]
[[Category: Zhou J]]