2j3s

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2j3s, resolution 2.50Å

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CRYSTAL STRUCTURE OF THE HUMAN FILAMIN A IG DOMAINS 19 TO 21

Contents

Overview

Human filamins are large actin-crosslinking proteins composed of an N-terminal actin-binding domain followed by 24 Ig-like domains (IgFLNs), which interact with numerous transmembrane receptors and cytosolic signaling proteins. Here we report the 2.5 A resolution structure of a three-domain fragment of human filamin A (IgFLNa19-21). The structure reveals an unexpected domain arrangement, with IgFLNa20 partially unfolded bringing IgFLNa21 into close proximity to IgFLNa19. Notably the N-terminus of IgFLNa20 forms a beta-strand that associates with the CD face of IgFLNa21 and occupies the binding site for integrin adhesion receptors. Disruption of this IgFLNa20-IgFLNa21 interaction enhances filamin binding to integrin beta-tails. Structural and functional analysis of other IgFLN domains suggests that auto-inhibition by adjacent IgFLN domains may be a general mechanism controlling filamin-ligand interactions. This can explain the increased integrin binding of filamin splice variants and provides a mechanism by which ligand binding might impact filamin structure.

Disease

Known diseases associated with this structure: Frontometaphyseal dysplasia OMIM:[300017], Heterotopia, periventricular OMIM:[300017], Heterotopia, periventricular nodular, with frontometaphyseal dysplasia OMIM:[300017], Heterotopia, periventricular, ED variant OMIM:[300017], Melnick-Needles syndrome OMIM:[300017], Otopalatodigital syndrome, type I OMIM:[300017], Otopalatodigital syndrome, type II OMIM:[300017]

About this Structure

2J3S is a Single protein structure of sequence from Homo sapiens with , and as ligands. Known structural/functional Sites: , , , , and . Full crystallographic information is available from OCA.

Reference

Structure of three tandem filamin domains reveals auto-inhibition of ligand binding., Lad Y, Kiema T, Jiang P, Pentikainen OT, Coles CH, Campbell ID, Calderwood DA, Ylanne J, EMBO J. 2007 Sep 5;26(17):3993-4004. Epub 2007 Aug 9. PMID:17690686

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