Hypertrophic cardiomyopathy (HCM) is one of the most common cardiomyopathies, and a major cause of sudden death in young athletes. The Ca2+ sensor of the sarcomere, cardiac troponin C (cTnC), plays an important role in regulating muscle contraction. Although several cardiomyopathy-causing mutations have been identified in cTnC, limited information about their structural defects has been mapped to the HCM phenotype. Here, we use high-resolution electron-spray ionization mass spectrometry (ESI-MS), Carr-Purcell-Meiboom-Gill relaxation dispersion (CPMG-RD) and affinity measurements of cTnC for the thin filament in reconstituted papillary muscles to provide evidence of an allosteric mechanism in mutant cTnC that may play a role to the HCM phenotype. We show that the D145E mutation leads to altered dynamics on a μs-ms timescale and deactivates both divalent-cation binding sites of the cTnC C-domain. CPMG-RD captured a low-populated conformation triggered by the Glu145 replacement of Asp. Paradoxically, although D145E C-domain is unable to bind Ca2+ or Mg2+, these changes along its backbone allowed it to attach more firmly to thin filaments than the wild-type isoform, providing evidence for an allosteric response of the Ca2+-binding site II in the N-domain. Our findings explain how the effects of an HCM mutation in the C-domain reflect up into the N-domain to cause an increase of Ca2+ affinity in site II, thus opening up new insights into the HCM phenotype.
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