1lmj

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NMR Study of the Fibrillin-1 cbEGF12-13 Pair of Ca2+ Binding Epidermal Growth Factor-like Domains

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Fibrillin-1 is a mosaic protein mainly composed of 43 calcium binding, epidermal growth factor-like (cbEGF) domains arranged as multiple, tandem, repeats. Mutations within the fibrillin-1 gene cause Marfan syndrome, (MFS), a heritable disease of connective tissue. More than 60% of, MFS-causing mutations identified are localized to cbEGFs, emphasizing that, the native properties of these domains are critical for fibrillin-1, function. The cbEGF12-13 domain pair is within the longest run of cbEGFs, and many mutations that cluster in this region are associated with severe, neonatal MFS. The NMR solution structure of Ca(2+)-loaded cbEGF12-13, exhibits a near-linear, rod-like arrangement of domains. This observation, supports the hypothesis that all fibrillin-1 (cb)EGF-cbEGF pairs, characterized by a single interdomain linker residue, possess this, rod-like structure. The domain arrangement of cbEGF12-13 is stabilized by, additional interdomain packing interactions to those observed for, cbEGF32-33, which may help to explain the previously reported higher, calcium binding affinity of cbEGF13. Based on this structure, a model of, cbEGF11-15 that encompasses all known neonatal MFS missense mutations has, highlighted a potential binding region. Backbone dynamics data confirm the, extended structure of cbEGF12-13 and lend support to the hypothesis that a, correlation exists between backbone flexibility and cbEGF domain calcium, affinity. These results provide important insight into the potential, consequences of MFS-associated mutations for the assembly and, biomechanical properties of connective tissue microfibrils.

Disease

Known diseases associated with this structure: Aortic aneurysm, ascending, and dissection OMIM:[134797], Ectopia lentis, familial OMIM:[134797], MASS syndrome OMIM:[134797], Marfan syndrome OMIM:[134797], Shprintzen-Goldberg syndrome OMIM:[134797], Weill-Marchesani syndrome, dominant OMIM:[134797]

About this Structure

1LMJ is a Single protein structure of sequence from Homo sapiens with CA as ligand. Full crystallographic information is available from OCA.

Reference

Solution structure and dynamics of a calcium binding epidermal growth factor-like domain pair from the neonatal region of human fibrillin-1., Smallridge RS, Whiteman P, Werner JM, Campbell ID, Handford PA, Downing AK, J Biol Chem. 2003 Apr 4;278(14):12199-206. Epub 2003 Jan 2. PMID:12511552

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