2lnk
Solution structure of Ca-bound S100A4 in complex with non-muscle myosin IIA
Structural highlights
DiseaseMYH9_HUMAN MYH9-related thrombocytopenia;Autosomal dominant nonsyndromic sensorineural deafness type DFNA. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Subjects with mutations in the motor domain of MYH9 present with severe thrombocytopenia and develop nephritis and deafness before the age of 40 years, while those with mutations in the tail domain have a much lower risk of noncongenital complications and significantly higher platelet counts. The clinical course of patients with mutations in the four most frequently affected residues of MYH9 (responsible for 70% of MYH9-related cases) were evaluated. Mutations at residue 1933 do not induce kidney damage or cataracts and cause deafness only in the elderly, those in position 702 result in severe thrombocytopenia and produce nephritis and deafness at a juvenile age, while alterations at residue 1424 or 1841 result in intermediate clinical pictures. Genetic variations in MYH9 are associated with non-diabetic end stage renal disease (ESRD). FunctionMYH9_HUMAN Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping. During cell spreading, plays an important role in cytoskeleton reorganization, focal contacts formation (in the margins but not the central part of spreading cells), and lamellipodial retraction; this function is mechanically antagonized by MYH10.[1] Publication Abstract from PubMedFilament assembly of nonmuscle myosin IIA (NMIIA) is selectively regulated by the small Ca(2+)-binding protein, S100A4, which causes enhanced cell migration and metastasis in certain cancers. Our NMR structure shows that an S100A4 dimer binds to a single myosin heavy chain in an asymmetrical configuration. NMIIA in the complex forms a continuous helix that stretches across the surface of S100A4 and engages the Ca(2+)-dependent binding sites of each subunit in the dimer. Synergy between these sites leads to a very tight association (K(D) approximately 1 nM) that is unique in the S100 family. Single-residue mutations that remove this synergy weaken binding and ameliorate the effects of S100A4 on NMIIA filament assembly and cell spreading in A431 human epithelial carcinoma cells. We propose a model for NMIIA filament disassembly by S100A4 in which initial binding to the unstructured NMIIA tail initiates unzipping of the coiled coil and disruption of filament packing. Asymmetric Mode of Ca(2+)-S100A4 Interaction with Nonmuscle Myosin IIA Generates Nanomolar Affinity Required for Filament Remodeling.,Elliott PR, Irvine AF, Jung HS, Tozawa K, Pastok MW, Picone R, Badyal SK, Basran J, Rudland PS, Barraclough R, Lian LY, Bagshaw CR, Kriajevska M, Barsukov IL Structure. 2012 Apr 4;20(4):654-66. Epub 2012 Apr 3. PMID:22483112[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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