View source for 4bbk


==Structural and functional characterisation of the kindlin-1 pleckstrin homology domain==
<StructureSection load='4bbk' size='340' side='right'caption='[[4bbk]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4bbk]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BBK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BBK 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]] 2.1&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></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=4bbk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bbk OCA], [https://pdbe.org/4bbk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bbk RCSB], [https://www.ebi.ac.uk/pdbsum/4bbk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bbk ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/FERM1_MOUSE FERM1_MOUSE] Involved in cell adhesion. Contributes to integrin activation. When coexpressed with talin, potentiates activation of ITGA2B. Required for normal keratinocyte proliferation. Required for normal polarization of basal keratinocytes in skin, and for normal cell shape. Required for normal adhesion of keratinocytes to fibronectin and laminin, and for normal keratinocyte migration to wound sites (By similarity).
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== Publication Abstract from PubMed ==
Inside-out activation of integrins is mediated via the binding of talin and kindlin to integrin beta-subunit cytoplasmic tails (CTs). The kindlin FERM domain is interrupted by a pleckstrin homology (PH) domain within its F2 subdomain. Here, we present data confirming the importance of the kindlin-1 PH domain for integrin activation, and its X-ray crystal structure at a resolution of 2.1 A revealing a C-terminal second alpha-helix integral to the domain but found only in the kindlin protein family. An isoform-specific salt-bridge occludes the canonical phosphoinositide binding site, but molecular dynamics (MD) simulations display transient switching to an alternative open conformer. Molecular docking reveals that the opening of the pocket would enable potential ligands to bind within it. Although lipid overlay assays suggested the PH domain binds inositol monophosphates, surface plasmon resonance (SPR) demonstrated weak affinities for Ins(3,4,5)P3 (KD ~100 muM) and no monophosphate binding. Removing the salt bridge by site-directed mutagenesis increases the PH domain affinity for Ins(3,4,5)P3 as measured by SPR, and enables it to bind PtdIns(3,5)P2 on a dot blot. Structural comparison with other PH domains suggests that the phosphate binding pocket in the kindlin-1 PH domain is more occluded than in kindlins -2 and -3 due to its salt bridge. In addition, the apparent affinity for Ins(3,4,5)P3 is affected by the presence of PO4 ions in the buffer. We suggest the physiological ligand of the kindlin-1 PH domain is most likely not an inositol phosphate but another phosphorylated species.

Structural and functional characterisation of the kindlin-1 pleckstrin homology domain.,Yates LA, Lumb CN, Brahme NN, Zalyte R, Bird LE, De Colibus L, Owens RJ, Calderwood DA, Sansom MS, Gilbert RJ J Biol Chem. 2012 Nov 6. PMID:23132860<ref>PMID:23132860</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 4bbk" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Bird LE]]
[[Category: Brahme NN]]
[[Category: Calderwood DA]]
[[Category: De Colibus L]]
[[Category: Gilbert RJC]]
[[Category: Lumb CN]]
[[Category: Owens RJ]]
[[Category: Sansom MSP]]
[[Category: Yates LA]]
[[Category: Zalyte R]]