2N79

The structural and functional effects of the Familial Hypertrophic Cardiomyopathy-linked cardiac troponin C mutation, L29Q

Summary for 2N79

• Entry DOI: 10.2210/pdb2n79/pdb
• Related: 1ap4 1r2u 2ctn 2mlf
• NMR Information: BMRB: 25797
• Descriptor: Troponin C, slow skeletal and cardiac muscles, CALCIUM ION (2 entities in total)
• Functional Keywords: cardiac, contractile protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 10093.22

Authors

Robertson, I.M.,Sevrieva, I.,Li, M.X.,Irving, M.,Sun, Y.,Sykes, B. (deposition date: 2015-09-06, release date: 2015-10-28, Last modification date: 2024-05-15)

Primary citation

Robertson, I.M.,Sevrieva, I.,Li, M.X.,Irving, M.,Sun, Y.B.,Sykes, B.D.
The structural and functional effects of the familial hypertrophic cardiomyopathy-linked cardiac troponin C mutation, L29Q.
J.MOL.CELL.CARDIOL., 87:257-269, 2015

PubMed 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 in demembranated ventricular trabeculae using fluorescence for in situ structure. L29Q reduced the cooperativity of the Ca(2+)-dependent structural change in cTnC in trabeculae under basal conditions and abolished the effect of force-generating myosin cross-bridges on this structural change. These effects could contribute to the pathogenesis of this mutation.

PubMed: 26341255
DOI: 10.1016/j.yjmcc.2015.08.017

Experimental method

SOLUTION NMR