9ihl
From Proteopedia
Crystal Structure of the Human Nonmuscle Myosin 2A Motor Domain
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] ACTNA_DICDI F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures. This is a bundling protein. Increases the actin-stimulated ATPase activity of myosin. Involved in vegetative cell growth, phagocytosis, motility and development, probably through stabilization of the actin network in the cortical cytoskeleton.[2] [3] [4] [5] [6] [7] [8] [9] Publication Abstract from PubMedNon-muscle myosin 2A (NM2A) is the predominant myosin isoform in non-muscle cells. Together with its paralogues NM2B and NM2C, NM2A enables tension and force generation, driving essential cellular processes such as membrane protrusion and retraction, directed migration, adhesion and cytokinesis. The NM2 isoforms display paralogue-specific mechanochemical characteristics that support their specific cellular functions. Here, we determined the structure of the human NM2A motor domain, addressing a critical gap in understanding myosin family diversification. Based on our experimentally resolved 2.1 A structure of the NM2A motor domain in its nucleotide-free state, we demonstrate, through integrative modeling of NM2-actin complexes and molecular dynamics simulations, how sequence differences between NM2A and NM2B underpin their functional specialization. Loop2 emerges as a critical determinant of isoform-specific behavior. Comparative analysis of ATP interaction fingerprints across NM2 isoforms reveals a conserved ATP binding mechanism. These findings illuminate an allosteric energy transduction pathway that connects sequence variation to actin-binding dynamics, providing mechanistic insight into isoform-specific cytoskeletal functions. Structure of the Human Non-Muscle Myosin 2A Motor Domain: Insights into Isoform-Specific Mechanochemistry.,Heiringhoff RS, Greve JN, Zahn M, Manstein DJ J Biol Chem. 2025 Sep 10:110691. doi: 10.1016/j.jbc.2025.110691. PMID:40939649[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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