An interplay between protein disorder and structure confers the Ca2+ regulation of striated muscle

Hoffman, Ryan M. B., Blumenschein, Tharin M. A. ORCID: https://orcid.org/0000-0002-4932-5178 and Sykes, Brian D. (2006) An interplay between protein disorder and structure confers the Ca2+ regulation of striated muscle. Journal of Molecular Biology, 361 (4). pp. 625-633. ISSN 1089-8638

Full text not available from this repository.

Abstract

The troponin (Tn) complex regulates the thin filament of striated muscle by transducing [Ca2+] fluctuations into conformational changes. These changes propagate to tropomyosin (Tm), which then assumes a new disposition with respect to actin, reversibly exposing actin's binding sites for the thick filament motor-ATPase (myosin). To date, the structural biology of thin filament regulation has been studied in the context of two equilibrium states corresponding to high (contraction-activated) and low (contraction-inhibited) sarcomeric [Ca2+]. New electron micrographic reconstructions of the thin filament have resolved Tn, actin, and Tm in high and low [Ca2+] states, integrating high-resolution structures of the Tn core, actin, and Tm. The resultant picture of thin filament regulation does not resolve all of the functionally significant portions of troponin I (TnI) or troponin C (TnC). Those regions of Tn have been shown (using NMR relaxation spectroscopy) to undergo conformational fluctuations, rationalizing the absence of these regions from micrograph-based reconstructions. The disordered portions of Tn are, to date, being interpreted within a canonical structure–activity paradigm. Here we present a new mechanism for the regulation of Tn having explicit descriptions of the kinetic pathways of activation and inhibition. Our thesis is that the intrinsic disorder of TnI is mechanistically significant. As the coupling of folding to binding has been shown to confer an inherent kinetic advantage (known as flycasting activity), our thesis accounts for TnI's conformational heterogeneity and known structure–activity relationships in a parsimonious fashion. We integrate recent NMR structures of the C-terminus of TnI and NMR observations of the conformational dynamics of the Tn complex into high-resolution models of the thin filament. Ways of evaluating the mechanism are discussed. The novel conceptual framework presented here prompts new hypotheses regarding the mechanism of pH sensitivity and of pathogenic mutations in troponin.

Item Type:	Article
Faculty \ School:	Faculty of Science > School of Chemistry (former - to 2024)
UEA Research Groups:	Faculty of Science > Research Groups > Chemistry of Life Processes Faculty of Science > Research Centres > Centre for Molecular and Structural Biochemistry Faculty of Science > Research Groups > Biophysical Chemistry (former - to 2017)
Depositing User:	Rachel Smith
Date Deposited:	15 Feb 2011 12:19
Last Modified:	24 Sep 2024 09:45
URI:	https://ueaeprints.uea.ac.uk/id/eprint/21375
DOI:	10.1016/j.jmb.2006.06.031

Actions (login required)

View Item