PDF(Pubmed)
Abstract：
Actin is a highly expressed protein in eukaryotic cells and is essential for numerous cellular processes. In particular, efficient striated muscle contraction is dependent upon the precise regulation of actin-based thin filament structure and function. Alterations in the lengths of actin-thin filaments can lead to the development of myopathies. Leiomodins and tropomodulins are members of an actin-binding protein family that fine-tune thin filament lengths, and their dysfunction is implicated in muscle diseases. An Lmod3 mutation [G326R] was previously identified in patients with nemaline myopathy (NM), a severe skeletal muscle disorder; this residue is conserved among Lmod and Tmod isoforms and resides within their homologous leucine-rich repeat (LRR) domain. We mutated this glycine to arginine in Lmod and Tmod to determine the physiological function of this residue and domain. This G-to-R substitution disrupts Lmod and Tmod\'s LRR domain structure, altering their binding interface with actin and destroying their abilities to regulate thin filament lengths. Additionally, this mutation renders Lmod3 nonfunctional in vivo. We found that one single amino acid is essential for folding of Lmod and Tmod LRR domains, and thus is essential for the opposing actin-regulatory functions of Lmod (filament elongation) and Tmod (filament shortening), revealing a mechanism underlying the development of NM.
摘要：
肌动蛋白是真核细胞中高度表达的蛋白质，对于许多细胞过程至关重要。特别是,有效的横纹肌收缩取决于基于肌动蛋白的细丝结构和功能的精确调节。肌动蛋白细丝长度的改变可导致肌病的发展。Leomoodins和营养调节蛋白是肌动蛋白结合蛋白家族的成员，可微调细丝长度，它们的功能障碍与肌肉疾病有关。先前在患有线虫肌病（NM）的患者中发现了Lmod3突变[G326R]，严重的骨骼肌疾病；该残基在Lmod和Tmod同工型中保守，并位于其同源的富含亮氨酸的重复（LRR）结构域内。我们在Lmod和Tmod中将该甘氨酸突变为精氨酸以确定该残基和结构域的生理功能。这种G到R替换破坏了Lmod和Tmod的LRR域结构，改变它们与肌动蛋白的结合界面并破坏它们调节细丝长度的能力。此外,这种突变使Lmod3在体内无功能。我们发现一个氨基酸对于Lmod和TmodLRR结构域的折叠是必不可少的，因此对于Lmod（细丝伸长）和Tmod（细丝缩短）的相反的肌动蛋白调节功能至关重要，揭示了NM发展的潜在机制。
