5l81

Crystal structure of the PH domain of murine kindlin-3

spinqualitylabelsall models 5l81, resolution 2.23Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5l81 is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.23Å Ligands: NA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function URP2_MOUSE Plays a central role in cell adhesion in hematopoietic cells (By similarity). Acts by activating the integrin beta-1-3 (ITGB1, ITGB2 and ITGB3) (PubMed:18278053). Required for integrin-mediated platelet adhesion and leukocyte adhesion to endothelial cells (PubMed:19234461). Required for activation of integrin beta-2 (ITGB2) in polymorphonuclear granulocytes (PMNs) (PubMed:18278053).[UniProtKB:Q86UX7] Publication Abstract from PubMed Kindlins co-activate integrins alongside talin. They possess, like talin, a FERM domain comprising F0-F3 subdomains, but with a pleckstrin homology (PH) domain inserted in the F2 subdomain that enables membrane association. We present the crystal structure of murine kindlin-3 PH domain determined at 2.23A resolution and characterise its lipid binding using biophysical and computational approaches. Molecular dynamics (MD) simulations suggest flexibility in the PH domain loops connecting beta-strands forming the putative phosphatidylinositol phosphate (PtdInsP) binding site. Simulations with PtdInsP-containing bilayers reveal that the PH domain associates with PtdInsP molecules mainly via the positively charged surface presented by the beta1-beta2 loop and that it binds with somewhat higher affinity to PtdIns(3,4,5)P3 compared to PtdIns(4,5)P2 Surface plasmon resonance (SPR) with lipid headgroups immobilised and the PH domain as analyte indicate affinities of 300 muM for PtdIns(3,4,5)P3 and 1mM for PtdIns(4,5)P2 In contrast, SPR studies with immobilised PH domain and lipid nanodiscs as analyte show affinities of 0.40 microM for PtdIns(3,4,5)P3 and no affinity for PtdIns(4,5)P2 when the inositol phosphate constitutes 5% of the total lipids (~5 molecules per nanodisc). Reducing the PtdIns(3,4,5)P3 composition to 1% abolishes nanodisc binding to the PH domain, as does site-directed mutagenesis of two lysines within the beta1-beta2 loop. Binding of PtdIns(3,4,5)P3 by a canonical PH domain, Grp1, is not similarly influenced by SPR experimental design. These data suggest a role for PtdIns(3,4,5)P3 clustering in the binding of some PH domains and not others, highlighting the importance lipid mobility and clustering for the biophysical assessment of protein-membrane interactions. Structure and lipid binding properties of the kindlin-3 pleckstrin homology domain.,Ni T, Kalli A, Naughton F, Yates L, Naneh O, Kozorog M, Anderluh G, Sansom M, Gilbert R Biochem J. 2016 Dec 14. pii: BCJ20160791. PMID:27974389 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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