Differential lipid binding of vinculin isoforms promotes quasi-equivalent dimerization

Journal Article · Mon Aug 08 00:00:00 EDT 2016 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1600702113· OSTI ID:1314256

Chinthalapudi, Krishna ^[1]; Rangarajan, Erumbi S. ^[1]; Brown, David T. ^[2]; Izard, Tina ^[1]

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1. The Scripps Research Inst., Jupiter, FL (United States)
2. Univ. of Mississippi Medical Center, Jackson, MS (United States)

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 invinculincan 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. Here, 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.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States)
• Sponsoring Organization: American Heart Association; Dept. of Defense; National Inst. of Health; The Scripps Research Inst.
• OSTI ID: 1314256
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 34 Vol. 113; ISSN 0027-8424
• Publisher: National Academy of Sciences
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
adhesion
cardiomyopathy
cell
cytoskeleton
metavinculin
vinculin