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{{STRUCTURE_3b71|  PDB=3b71  |  SCENE=  }}
===CD4 endocytosis motif bound to the Focal Adhesion Targeting (FAT) domain of the Focal Adhesion Kinase===
{{ABSTRACT_PUBMED_18078954}}


==Disease==
==CD4 endocytosis motif bound to the Focal Adhesion Targeting (FAT) domain of the Focal Adhesion Kinase==
[[http://www.uniprot.org/uniprot/FAK1_HUMAN FAK1_HUMAN]] Note=Aberrant PTK2/FAK1 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. PTK2/FAK1 overexpression is seen in many types of cancer.<ref>PMID:11980671</ref><ref>PMID:18006843</ref><ref>PMID:17395594</ref><ref>PMID:17431114</ref><ref>PMID:19147981</ref><ref>PMID:20495381</ref><ref>PMID:16919435</ref><ref>PMID:18677107</ref><ref>PMID:19224453</ref>  
<StructureSection load='3b71' size='340' side='right'caption='[[3b71]], [[Resolution|resolution]] 2.82&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3b71]] is a 6 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=3B71 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3B71 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]] 2.82&#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=3b71 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3b71 OCA], [https://pdbe.org/3b71 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3b71 RCSB], [https://www.ebi.ac.uk/pdbsum/3b71 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3b71 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/FAK1_HUMAN FAK1_HUMAN] Note=Aberrant PTK2/FAK1 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. PTK2/FAK1 overexpression is seen in many types of cancer.<ref>PMID:11980671</ref> <ref>PMID:18006843</ref> <ref>PMID:17395594</ref> <ref>PMID:17431114</ref> <ref>PMID:19147981</ref> <ref>PMID:20495381</ref> <ref>PMID:16919435</ref> <ref>PMID:18677107</ref> <ref>PMID:19224453</ref>  
== Function ==
[https://www.uniprot.org/uniprot/FAK1_HUMAN FAK1_HUMAN] 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 and placenta development. Required for 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), EPHA2, 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. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription.<ref>PMID:10655584</ref> <ref>PMID:11331870</ref> <ref>PMID:11980671</ref> <ref>PMID:15166238</ref> <ref>PMID:15561106</ref> <ref>PMID:15895076</ref> <ref>PMID:18006843</ref> <ref>PMID:17395594</ref> <ref>PMID:16927379</ref> <ref>PMID:17431114</ref> <ref>PMID:18497331</ref> <ref>PMID:18292575</ref> <ref>PMID:18256281</ref> <ref>PMID:18206965</ref> <ref>PMID:19138410</ref> <ref>PMID:19147981</ref> <ref>PMID:20495381</ref> <ref>PMID:20109444</ref> <ref>PMID:21454698</ref> <ref>PMID:16919435</ref> <ref>PMID:18677107</ref> <ref>PMID:19224453</ref>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/b7/3b71_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3b71 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Focal adhesion kinase (FAK) and CD4 fulfil vital functions in cellular signal transduction: FAK is a central component in integrin signalling, whereas CD4 plays essential roles in the immune defence. In T lymphocytes, FAK and CD4 localise to the same signalling complexes after stimulation by either the human immunodeficiency virus (HIV) gp120 glycoprotein or an antigen, suggesting the concerted action of FAK and CD4 in these cells. Using crystallography and microcalorimetry, we here show that the focal adhesion targeting (FAT) domain of FAK binds specifically to the CD4 endocytosis motif in vitro. This FAT-CD4 complex is structurally and thermodynamically similar to the one FAT forms with paxillin LD motifs. The CD4 binding site on FAT presents the same features as the established CD4 binding site on the HIV-1 Nef protein. The binding of FAT to CD4 is incompatible with the binding of Lck to CD4. We further show that HIV-1 gp120 triggers the association of CD4 with FAK in T cells, under conditions that are known to dissociate Lck from CD4. Our results suggest that the FAK-CD4 complex represents an alternative route for eliciting T-cell-specific signals and that it links gp120 engagement to distinctive T-cell signalling during HIV infection. In infected cells, HIV-1 Nef may displace FAK from CD4 to protect the cells from apoptosis.


==Function==
Structural basis for the interaction between focal adhesion kinase and CD4.,Garron ML, Arthos J, Guichou JF, McNally J, Cicala C, Arold ST J Mol Biol. 2008 Feb 1;375(5):1320-8. Epub 2007 Nov 22. PMID:18078954<ref>PMID:18078954</ref>
[[http://www.uniprot.org/uniprot/FAK1_HUMAN FAK1_HUMAN]] 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 and placenta development. Required for 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), EPHA2, 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. Recruits the ubiquitin ligase MDM2 to P53/TP53 in the nucleus, and thereby regulates P53/TP53 activity, P53/TP53 ubiquitination and proteasomal degradation. Phosphorylates SRC; this increases SRC kinase activity. Phosphorylates ACTN1, ARHGEF7, GRB7, RET and WASL. Promotes phosphorylation of PXN and STAT1; most likely PXN and STAT1 are phosphorylated by a SRC family kinase that is recruited to autophosphorylated PTK2/FAK1, rather than by PTK2/FAK1 itself. Promotes phosphorylation of BCAR1; GIT2 and SHC1; this requires both SRC and PTK2/FAK1. Promotes phosphorylation of BMX and PIK3R1. Isoform 6 (FRNK) does not contain a kinase domain and inhibits PTK2/FAK1 phosphorylation and signaling. Its enhanced expression can attenuate the nuclear accumulation of LPXN and limit its ability to enhance serum response factor (SRF)-dependent gene transcription.<ref>PMID:10655584</ref><ref>PMID:11331870</ref><ref>PMID:11980671</ref><ref>PMID:15166238</ref><ref>PMID:15561106</ref><ref>PMID:15895076</ref><ref>PMID:18006843</ref><ref>PMID:17395594</ref><ref>PMID:16927379</ref><ref>PMID:17431114</ref><ref>PMID:18497331</ref><ref>PMID:18292575</ref><ref>PMID:18256281</ref><ref>PMID:18206965</ref><ref>PMID:19138410</ref><ref>PMID:19147981</ref><ref>PMID:20495381</ref><ref>PMID:20109444</ref><ref>PMID:21454698</ref><ref>PMID:16919435</ref><ref>PMID:18677107</ref><ref>PMID:19224453</ref> [[http://www.uniprot.org/uniprot/CD4_HUMAN CD4_HUMAN]] Accessory protein for MHC class-II antigen/T-cell receptor interaction. May regulate T-cell activation. Induces the aggregation of lipid rafts.


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[3b71]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3B71 OCA].
</div>
<div class="pdbe-citations 3b71" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Focal adhesion kinase|Focal adhesion kinase]]
*[[CD4 3D structures|CD4 3D structures]]
 
*[[Focal adhesion kinase 3D structures|Focal adhesion kinase 3D structures]]
==Reference==
== References ==
<ref group="xtra">PMID:018078954</ref><references group="xtra"/><references/>
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Non-specific protein-tyrosine kinase]]
[[Category: Large Structures]]
[[Category: Arold, S T.]]
[[Category: Arold ST]]
[[Category: Garron, M L.]]
[[Category: Garron M-L]]
[[Category: Atp-binding]]
[[Category: Cell junction]]
[[Category: Four-helix bundle]]
[[Category: Glycoprotein]]
[[Category: Host-virus interaction]]
[[Category: Immune response]]
[[Category: Immunoglobulin domain]]
[[Category: Kinase]]
[[Category: Lipoprotein]]
[[Category: Membrane]]
[[Category: Nucleotide-binding]]
[[Category: Palmitate]]
[[Category: Phosphorylation]]
[[Category: Protein binding]]
[[Category: Protein-protein complex]]
[[Category: Transferase]]
[[Category: Transmembrane]]
[[Category: Tyrosine-protein kinase]]

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