The structural and functional effects of the familial hypertrophic cardiomyopathy-linked cardiac troponin C mutation, L29Q.

Journal of Molecular and Cellular Cardiology
Ian M RobertsonBrian D Sykes

Abstract

Familial hypertrophic cardiomyopathy (FHC) is characterized by severe abnormal cardiac muscle growth. The traditional view of disease progression in FHC is that an increase in the Ca(2+)-sensitivity of cardiac muscle contraction ultimately leads to pathogenic myocardial remodeling, though recent studies suggest this may be an oversimplification. For example, FHC may be developed through altered signaling that prevents downstream regulation of contraction. The mutation L29Q, found in the Ca(2+)-binding regulatory protein in heart muscle, cardiac troponin C (cTnC), has been linked to cardiac hypertrophy. However, reports on the functional effects of this mutation are conflicting, and our goal was to combine in vitro and in situ structural and functional data to elucidate its mechanism of action. We used nuclear magnetic resonance and circular dichroism to solve the structure and characterize the backbone dynamics and stability of the regulatory domain of cTnC with the L29Q mutation. The overall structure and dynamics of cTnC were unperturbed, although a slight rearrangement of site 1, an increase in backbone flexibility, and a small decrease in protein stability were observed. The structure and function of cTnC was also assessed ...Continue Reading

References

Jul 26, 1972·Nature: New Biology·R D Bremel, A Weber
Sep 1, 1995·Nature Structural Biology·S M GagnéB D Sykes
Nov 1, 1995·Journal of Biomolecular NMR·F DelaglioA Bax
Jul 18, 1997·The Journal of Biological Chemistry·S K SiaB D Sykes
Apr 21, 1998·Bioconjugate Chemistry·J E CorrieV R Munasinghe
Sep 19, 2002·The Journal of Biological Chemistry·Douglas G WardIan P Trayer
Jan 10, 2003·American Journal of Physiology. Cell Physiology·Todd E GillisGlen F Tibbits
Jan 31, 2003·Proteins·Jens P LingeMichael Nilges
Feb 5, 2003·Journal of Magnetic Resonance·Charles D SchwietersG Marius Clore
Aug 27, 2003·Biochemistry·Douglas G WardIan P Trayer
Apr 28, 2004·Biochemistry·Tharin M A BlumenscheinBrian D Sykes
Jun 19, 2004·The Journal of Biological Chemistry·Svetlana B Tikunova, Jonathan P Davis
Mar 2, 2005·Progress in Cardiovascular Diseases·Michael S Parmacek, R John Solaro
Mar 24, 2005·Physiological Genomics·Todd E GillisGlen F Tibbits
Dec 29, 2007·Biochemical and Biophysical Research Communications·Monica X LiBrian D Sykes
Apr 10, 2008·Journal of Biomolecular NMR·Olga K BaryshnikovaBrian D Sykes
Jun 24, 2008·Journal of Molecular and Cellular Cardiology·Andrew P LandstromMichael J Ackerman
Nov 19, 2008·The Journal of Physiology·Yin-Biao SunMalcolm Irving
Nov 17, 2009·Journal of Molecular and Cellular Cardiology·Ruth H WillottJames D Potter
Jan 25, 2011·The Journal of Biological Chemistry·R John Solaro, Tomoyoshi Kobayashi
Jun 28, 2011·Circulation Research·Houman AshrafianHugh Watkins
Jul 30, 2011·Biochemistry·Edward P ManningSteven D Schwartz
May 15, 2012·Journal of Molecular Biology·Edward P ManningSteven D Schwartz

❮ Previous
Next ❯

Citations

Oct 11, 2016·Frontiers in Physiology·Mayra de A Marques, Guilherme A P de Oliveira
May 24, 2017·The Journal of Biological Chemistry·Charles M StevensGlen F Tibbits
Jan 5, 2017·The Journal of Biological Chemistry·Mayra de A MarquesGuilherme A P de Oliveira
Apr 9, 2020·Frontiers in Physiology·Alfredo Jesus López-DávilaRobert Stehle
Apr 29, 2019·Journal of Muscle Research and Cell Motility·Steven Marston, Juan Eiros Zamora

❮ Previous
Next ❯

Methods Mentioned

BETA
cross-linking studies
X-ray
nuclear
circular dichroism
NMR
Fluorescence

Software Mentioned

WinMAXC
CYANA
NIH
NMRPipe
Mathematica
FISS
BioPack
Smartnotebook
TALOS
ORBplus

Related Concepts

Related Feeds

Cardiac Remodeling

Cardiac remodeling in response to a myocardial infarction is characterized by progressive ventricular dilatation, cardiac hypertrophy, fibrosis, and deterioration of cardiac performance. Discover the latest research on Cardiac Remodeling here.

Cardiomyopathy

Cardiomyopathy is a disease of the heart muscle, that can lead to muscular or electrical dysfunction of the heart. It is often an irreversible disease that is associated with a poor prognosis. There are different causes and classifications of cardiomyopathies. Here are the latest discoveries pertaining to this disease.

Atrial Fibrillation

Atrial fibrillation is a common arrhythmia that is associated with substantial morbidity and mortality, particularly due to stroke and thromboembolism. Here is the latest research.

Calcium & Bioenergetics

Bioenergetic processes, including cellular respiration and photosynthesis, concern the transformation of energy by cells. Here is the latest research on the role of calcium in bioenergetics.

Cardiomegaly

Cardiomegaly, known as an enlarged heart, is a multifactorial disease with different pathophysiological mechanisms. Hypertension, pregnancy, exercise-induced and idiopathic causes are some mechanisms of cardiomegaly. Discover the latest research of cardiomegaly here.

Cardiovascular Homeostasis

Cardiovascular regulation and homeostasis is important in maintaining health and dysfunction may lead to cardiovascular diseases. Nitric oxide and vascular endothelium are one of many molecules involved in the homeostatic mechanism. Here is the latest research on cardiovascular homeostasis.

Arrhythmia

Arrhythmias are abnormalities in heart rhythms, which can be either too fast or too slow. They can result from abnormalities of the initiation of an impulse or impulse conduction or a combination of both. Here is the latest research on arrhythmias.