Familial Hypertrophic Cardiomyopathy-linked Alterations in Ca2+ Binding of Human Cardiac Myosin Regulatory Light Chain Affect Cardiac Muscle Contraction

Danuta Szczesna-Cordary, Georgianna Guzman, Shuk Shin Ng, Jiaju Zhao

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

The ventricular isoform of human cardiac regulatory light chain (HCRLC) has been shown to be one of the sarcomeric proteins associated with familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disease characterized by left ventricular and/or septal hypertrophy, myofibrillar disarray, and sudden cardiac death. Our recent studies have demonstrated that the properties of isolated HCRLC could be significantly altered by the FHC mutations and that their detrimental effects depend upon the specific position of the missense mutation. This report reveals that the Ca2+ sensitivity of myofibrillar ATPase activity and steady-state force development are also likely to change with the location of the specific FHC HCRLC mutation. The largest effect was seen for the two FHC mutations, N47K and R58Q, located directly in or near the single Ca2+-Mg2+ binding site of HCRLC, which demonstrated no Ca2+ binding compared with wild-type and other FHC mutants (A13T, F18L, E22K, P95A). These two mutants when reconstituted in porcine cardiac muscle preparations increased Ca2+ sensitivity of myofibrillar ATPase activity and force development. These results suggest the importance of the intact Ca2+ binding site of HCRLC in the regulation of cardiac muscle contraction and imply its possible role in the regulatory light chain-linked pathogenesis of FHC.

Original languageEnglish
Pages (from-to)3535-3542
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number5
DOIs
StatePublished - Jan 30 2004

Fingerprint

Familial Hypertrophic Cardiomyopathy
Cardiac Myosins
Myosin Light Chains
Muscle Contraction
Muscle
Myocardium
Light
Mutation
Adenosine Triphosphatases
Binding Sites
Sudden Cardiac Death
Missense Mutation
Hypertrophy
Protein Isoforms
Swine

ASJC Scopus subject areas

  • Biochemistry

Cite this

Familial Hypertrophic Cardiomyopathy-linked Alterations in Ca2+ Binding of Human Cardiac Myosin Regulatory Light Chain Affect Cardiac Muscle Contraction. / Szczesna-Cordary, Danuta; Guzman, Georgianna; Ng, Shuk Shin; Zhao, Jiaju.

In: Journal of Biological Chemistry, Vol. 279, No. 5, 30.01.2004, p. 3535-3542.

Research output: Contribution to journalArticle

@article{fd26f8235714402ba554979012f908fa,
title = "Familial Hypertrophic Cardiomyopathy-linked Alterations in Ca2+ Binding of Human Cardiac Myosin Regulatory Light Chain Affect Cardiac Muscle Contraction",
abstract = "The ventricular isoform of human cardiac regulatory light chain (HCRLC) has been shown to be one of the sarcomeric proteins associated with familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disease characterized by left ventricular and/or septal hypertrophy, myofibrillar disarray, and sudden cardiac death. Our recent studies have demonstrated that the properties of isolated HCRLC could be significantly altered by the FHC mutations and that their detrimental effects depend upon the specific position of the missense mutation. This report reveals that the Ca2+ sensitivity of myofibrillar ATPase activity and steady-state force development are also likely to change with the location of the specific FHC HCRLC mutation. The largest effect was seen for the two FHC mutations, N47K and R58Q, located directly in or near the single Ca2+-Mg2+ binding site of HCRLC, which demonstrated no Ca2+ binding compared with wild-type and other FHC mutants (A13T, F18L, E22K, P95A). These two mutants when reconstituted in porcine cardiac muscle preparations increased Ca2+ sensitivity of myofibrillar ATPase activity and force development. These results suggest the importance of the intact Ca2+ binding site of HCRLC in the regulation of cardiac muscle contraction and imply its possible role in the regulatory light chain-linked pathogenesis of FHC.",
author = "Danuta Szczesna-Cordary and Georgianna Guzman and Ng, {Shuk Shin} and Jiaju Zhao",
year = "2004",
month = "1",
day = "30",
doi = "10.1074/jbc.M307092200",
language = "English",
volume = "279",
pages = "3535--3542",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "5",

}

TY - JOUR

T1 - Familial Hypertrophic Cardiomyopathy-linked Alterations in Ca2+ Binding of Human Cardiac Myosin Regulatory Light Chain Affect Cardiac Muscle Contraction

AU - Szczesna-Cordary, Danuta

AU - Guzman, Georgianna

AU - Ng, Shuk Shin

AU - Zhao, Jiaju

PY - 2004/1/30

Y1 - 2004/1/30

N2 - The ventricular isoform of human cardiac regulatory light chain (HCRLC) has been shown to be one of the sarcomeric proteins associated with familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disease characterized by left ventricular and/or septal hypertrophy, myofibrillar disarray, and sudden cardiac death. Our recent studies have demonstrated that the properties of isolated HCRLC could be significantly altered by the FHC mutations and that their detrimental effects depend upon the specific position of the missense mutation. This report reveals that the Ca2+ sensitivity of myofibrillar ATPase activity and steady-state force development are also likely to change with the location of the specific FHC HCRLC mutation. The largest effect was seen for the two FHC mutations, N47K and R58Q, located directly in or near the single Ca2+-Mg2+ binding site of HCRLC, which demonstrated no Ca2+ binding compared with wild-type and other FHC mutants (A13T, F18L, E22K, P95A). These two mutants when reconstituted in porcine cardiac muscle preparations increased Ca2+ sensitivity of myofibrillar ATPase activity and force development. These results suggest the importance of the intact Ca2+ binding site of HCRLC in the regulation of cardiac muscle contraction and imply its possible role in the regulatory light chain-linked pathogenesis of FHC.

AB - The ventricular isoform of human cardiac regulatory light chain (HCRLC) has been shown to be one of the sarcomeric proteins associated with familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disease characterized by left ventricular and/or septal hypertrophy, myofibrillar disarray, and sudden cardiac death. Our recent studies have demonstrated that the properties of isolated HCRLC could be significantly altered by the FHC mutations and that their detrimental effects depend upon the specific position of the missense mutation. This report reveals that the Ca2+ sensitivity of myofibrillar ATPase activity and steady-state force development are also likely to change with the location of the specific FHC HCRLC mutation. The largest effect was seen for the two FHC mutations, N47K and R58Q, located directly in or near the single Ca2+-Mg2+ binding site of HCRLC, which demonstrated no Ca2+ binding compared with wild-type and other FHC mutants (A13T, F18L, E22K, P95A). These two mutants when reconstituted in porcine cardiac muscle preparations increased Ca2+ sensitivity of myofibrillar ATPase activity and force development. These results suggest the importance of the intact Ca2+ binding site of HCRLC in the regulation of cardiac muscle contraction and imply its possible role in the regulatory light chain-linked pathogenesis of FHC.

UR - http://www.scopus.com/inward/record.url?scp=0942276371&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0942276371&partnerID=8YFLogxK

U2 - 10.1074/jbc.M307092200

DO - 10.1074/jbc.M307092200

M3 - Article

VL - 279

SP - 3535

EP - 3542

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 5

ER -