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2lko

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Structural Basis of Phosphoinositide Binding to Kindlin-2 Pleckstrin Homology Domain in Regulating Integrin Activation

Structural highlights

2lko is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Solution NMR
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

FERM2_HUMAN Scaffolding protein that enhances integrin activation mediated by TLN1 and/or TLN2, but activates integrins only weakly by itself. Binds to membranes enriched in phosphoinositides. Enhances integrin-mediated cell adhesion onto the extracellular matrix and cell spreading; this requires both its ability to interact with integrins and with phospholipid membranes. Required for the assembly of focal adhesions. Participates in the connection between extracellular matrix adhesion sites and the actin cytoskeleton and also in the orchestration of actin assembly and cell shape modulation. Recruits FBLIM1 to focal adhesions. Plays a role in the TGFB1 and integrin signaling pathways. Stabilizes active CTNNB1 and plays a role in the regulation of transcription mediated by CTNNB1 and TCF7L2/TCF4 and in Wnt signaling.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Kindlins are a subclass of FERM-containing proteins that have recently emerged as key regulators of integrin receptor activation and signaling. As compared with the conventional FERM domain, the kindlin FERM domain contains an inserted pleckstrin homology (PH) domain that recognizes membrane phosphoinositides, including phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-trisphosphate (PIP3). Using NMR spectroscopy, we show that PIP3 site-specifically binds to kindlin-2 PH with substantial chemical shift changes that are much larger than PIP2. This suggests an enhanced association of kindlin-2 with membrane as mediated by PIP3 upon its conversion from PIP2 by phosphoinositide-3 kinase, a known regulator of integrin activation. We determined the NMR structure of the kindlin-2 PH domain bound to the head group of PIP3, inositol 1,3,4,5-tetraphosphate (IP4). The structure reveals a canonical PH domain fold, yet with a distinct IP4 binding pocket that appears highly conserved for the kindlin family members. Functional experiments demonstrate that although wild type kindlin-2 is capable of cooperating with integrin activator talin to induce synergistic integrin alpha(IIb)beta(3) activation, this ability is significantly impaired for a phosphoinositide binding-defective kindlin-2 mutant. These results define a specific PIP3 recognition mode for the kindlin PH domain. Moreover, they shed light upon a mechanism as to how the PH domain mediates membrane engagement of kindlin-2 to promote its binding to integrin and cooperation with talin for regulation of integrin activation.

Structural basis of phosphoinositide binding to kindlin-2 protein pleckstrin homology domain in regulating integrin activation.,Liu J, Fukuda K, Xu Z, Ma YQ, Hirbawi J, Mao X, Wu C, Plow EF, Qin J J Biol Chem. 2011 Dec 16;286(50):43334-42. Epub 2011 Oct 26. PMID:22030399^[7]

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

References

↑ Tu Y, Wu S, Shi X, Chen K, Wu C. Migfilin and Mig-2 link focal adhesions to filamin and the actin cytoskeleton and function in cell shape modulation. Cell. 2003 Apr 4;113(1):37-47. PMID:12679033
↑ Ma YQ, Qin J, Wu C, Plow EF. Kindlin-2 (Mig-2): a co-activator of beta3 integrins. J Cell Biol. 2008 May 5;181(3):439-46. doi: 10.1083/jcb.200710196. PMID:18458155 doi:http://dx.doi.org/10.1083/jcb.200710196
↑ Qu H, Tu Y, Shi X, Larjava H, Saleem MA, Shattil SJ, Fukuda K, Qin J, Kretzler M, Wu C. Kindlin-2 regulates podocyte adhesion and fibronectin matrix deposition through interactions with phosphoinositides and integrins. J Cell Sci. 2011 Mar 15;124(Pt 6):879-91. doi: 10.1242/jcs.076976. Epub 2011 Feb , 15. PMID:21325030 doi:http://dx.doi.org/10.1242/jcs.076976
↑ Yu Y, Wu J, Wang Y, Zhao T, Ma B, Liu Y, Fang W, Zhu WG, Zhang H. Kindlin 2 forms a transcriptional complex with beta-catenin and TCF4 to enhance Wnt signalling. EMBO Rep. 2012 Aug;13(8):750-8. doi: 10.1038/embor.2012.88. Epub 2012 Jun 15. PMID:22699938 doi:http://dx.doi.org/10.1038/embor.2012.88
↑ Liu J, Fukuda K, Xu Z, Ma YQ, Hirbawi J, Mao X, Wu C, Plow EF, Qin J. Structural basis of phosphoinositide binding to kindlin-2 protein pleckstrin homology domain in regulating integrin activation. J Biol Chem. 2011 Dec 16;286(50):43334-42. Epub 2011 Oct 26. PMID:22030399 doi:10.1074/jbc.M111.295352
↑ Perera HD, Ma YQ, Yang J, Hirbawi J, Plow EF, Qin J. Membrane Binding of the N-Terminal Ubiquitin-Like Domain of kindlin-2 Is Crucial for Its Regulation of Integrin Activation. Structure. 2011 Nov 9;19(11):1664-71. PMID:22078565 doi:10.1016/j.str.2011.08.012
↑ Liu J, Fukuda K, Xu Z, Ma YQ, Hirbawi J, Mao X, Wu C, Plow EF, Qin J. Structural basis of phosphoinositide binding to kindlin-2 protein pleckstrin homology domain in regulating integrin activation. J Biol Chem. 2011 Dec 16;286(50):43334-42. Epub 2011 Oct 26. PMID:22030399 doi:10.1074/jbc.M111.295352

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2lko"

Categories: Homo sapiens | Large Structures | Fukuda K | Liu J | Xu Z

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[2lko]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LKO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LKO FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4IP:INOSITOL-(1,3,4,5)-TETRAKISPHOSPHATE'>4IP</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4IP:INOSITOL-(1,3,4,5)-TETRAKISPHOSPHATE'>4IP</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=2lko FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2lko OCA], [https://pdbe.org/2lko PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2lko RCSB], [https://www.ebi.ac.uk/pdbsum/2lko PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2lko ProSAT]</span></td></tr>
 </table>

2lko

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Current revision

Structural Basis of Phosphoinositide Binding to Kindlin-2 Pleckstrin Homology Domain in Regulating Integrin Activation

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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