5L0C

Human metavinculin (residues 959-1134) in complex with PIP2

5L0C の概要

• エントリーDOI: 10.2210/pdb5l0c/pdb
• 分子名称: Vinculin, [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate, PHOSPHATE ION, ... (4 entities in total)
• 機能のキーワード: 5-helix bundle, cytoskelatal protein, lipids, cell adhesion, structural protein
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cell membrane ; Peripheral membrane protein ; Cytoplasmic side : P18206
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 82496.53

構造登録者

Chinthalapudi, K.,Izard, T. (登録日: 2016-07-27, 公開日: 2016-08-31, 最終更新日: 2023-10-04)

主引用文献

Chinthalapudi, K.,Rangarajan, E.S.,Brown, D.T.,Izard, T.
Differential lipid binding of vinculin isoforms promotes quasi-equivalent dimerization.
Proc.Natl.Acad.Sci.USA, 113:9539-9544, 2016

PubMed Abstract: The main cause of death globally remains debilitating heart conditions, such as dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), which are often due to mutations of specific components of adhesion complexes. Vinculin regulates these complexes and plays essential roles in intercalated discs that are necessary for muscle cell function and coordinated movement and in the development and function of the heart. Humans bearing familial or sporadic mutations in vinculin suffer from chronic, progressively debilitating DCM that ultimately leads to cardiac failure and death, whereas autosomal dominant mutations in vinculin can also provoke HCM, causing acute cardiac failure. The DCM/HCM-associated mutants of vinculin occur in the 68-residue insert unique to the muscle-specific, alternatively spliced isoform of vinculin, termed metavinculin (MV). Contrary to studies that suggested that phosphoinositol-4,5-bisphosphate (PIP2) only induces vinculin homodimers, which are asymmetric, we show that phospholipid binding results in a domain-swapped symmetric MV dimer via a quasi-equivalent interface compared with vinculin involving R975. Although one of the two PIP2 binding sites is preserved, the symmetric MV dimer that bridges two PIP2 molecules differs from the asymmetric vinculin dimer that bridges only one PIP2 Unlike vinculin, wild-type MV and the DCM/HCM-associated R975W mutant bind PIP2 in their inactive conformations, and R975W MV fails to dimerize. Mutating selective vinculin residues to their corresponding MV residues, or vice versa, switches the isoform's dimeric constellation and lipid binding site. Collectively, our data suggest that MV homodimerization modulates microfilament attachment at muscular adhesion sites and furthers our understanding of MV-mediated cardiac remodeling.

PubMed: 27503891
DOI: 10.1073/pnas.1600702113

実験手法

X-RAY DIFFRACTION (3.1 Å)