title: Cardiac troponin structure-function and the influence of hypertrophic cardiomyopathy associated mutations on modulation of contractility.
abstract: Cardiac troponin (cTn) acts as a pivotal regulator of muscle contraction and relaxation and is composed of three distinct subunits (cTnC: a highly conserved Ca(2+) binding subunit, cTnI: an actomyosin ATPase inhibitory subunit, and cTnT: a tropomyosin binding subunit). In this mini-review, we briefly summarize the structure-function relationship of cTn and its subunits, its modulation by PKA-mediated phosphorylation of cTnI, and what is known about how these properties are altered by hypertrophic cardiomyopathy (HCM) associated mutations of cTnI. This includes recent work using computational modeling approaches to understand the atomic-based structural level basis of disease-associated mutations. We propose a viewpoint that it is alteration of cTnC-cTnI interaction (rather than the Ca(2+) binding properties of cTn) per se that disrupt the ability of PKA-mediated phosphorylation at cTnI Ser-23/24 to alter contraction and relaxation in at least some HCM-associated mutations. The combination of state of the art biophysical approaches can provide new insight on the structure-function mechanisms of contractile dysfunction resulting cTnI mutations and exciting new avenues for the diagnosis, prevention, and even treatment of heart diseases.
authors: University of Washington, Department of Bioengineering, Seattle, WA, USA.
authors: Yuanhua
authors: Y
authors: Cheng
authors: University of Washington, Department of Bioengineering, Seattle, WA, USA. Electronic address: mregnier@uw.edu.
authors: Michael
authors: M
authors: Regnier
mesh_terms: D000818:Animals; D002118:Calcium / Q000737:chemistry; D002312:Cardiomyopathy, Hypertrophic / Q000378:metabolism*; D003198:Computer Simulation; D006801:Humans; D009154:Mutation; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D011499:Protein Processing, Post-Translational; D013329:Structure-Activity Relationship; D014335:Tropomyosin / Q000737:chemistry; D014336:Troponin / Q000737:chemistry* / Q000502:physiology*; D019209:Troponin C / Q000737:chemistry; D019210:Troponin I / Q000737:chemistry; D020107:Troponin T / Q000737:chemistry
chemical_list: D014335:Tropomyosin; D014336:Troponin; D019209:Troponin C; D019210:Troponin I; D020107:Troponin T; D002118:Calcium
keywords: Cardiac troponin; Hypertrophic cardiomyopathy; Mutation; PKA phosphorylation; Structure-function relationship; cTnC-cTnI interaction