A myomesin mutation associated with hypertrophic cardiomyopathy deteriorates dimerisation properties.
Myomesin plays an important structural and functional role in the M-band of striated muscles. The C-terminal domain 13 of myomesin dimerises and forms antiparallel strands which cross-link neighboring Myosin filaments and titin in the M-line of the sarcomeres. These interactions stabilise the contractile apparatus during striated muscle contraction. Since myomesin is an important component of the M-band we screened the myomesin gene for genetic variants in patients with hypertrophic cardiomyopathy (HCM). We identified the missense mutation V1490I in domain 12 of myomesin in a family with inherited HCM. Analytical ultracentrifugation experiments, circular dichroism spectra, and surface plasmon resonance spectroscopy of myomesin fragments were carried out to investigate the effects of the mutation V1490I on structure and function of myomesin domains 11-13 and 12-13. Both the wild type and mutated myomesin domains My11-13 revealed similar secondary structures and formed stable dimers. Mutated myomesin domains My11-13 and My12-13 dimers revealed a reduced thermal stability and a significantly decreased dimerisation affinity, showing disturbed functional properties of V1490I mutated myomesin. However, monomeric myomesin domains My11-12, i.e. without dimerisation domain 13 showed no difference in thermal stability between wild type and V1490I mutated myomesin. In conclusion, the V1490I mutation associated with HCM lead to myomesin proteins with abnormal functional properties which affect dimerisation properties of myomesin domain 13. These effects may contribute to the pathogenesis of HCM.
Max-Delbrück-Center for Molecular Medicine, Department of Molecular Muscle Physiology, Robert-Rössle Str.10, 13125 Berlin, Germany. romy_siegert@mdc-berlin.de
Romy
R
Siegert
Andreas
A
Perrot
Sandro
S
Keller
Joachim
J
Behlke
Aleksandra
A
Michalewska-Włudarczyk
Anna
A
Wycisk
Michal
M
Tendera
Ingo
I
Morano
Cemil
C
Ozcelik
D000328:Adult; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D064211:Connectin; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D020125:Mutation, Missense; D010375:Pedigree; D011487:Protein Conformation; D055503:Protein Multimerization; D020349:Surface Plasmon Resonance
D064211:Connectin; D009124:Muscle Proteins