The effects of cardiomyopathy-associated mutations in the head-to-tail overlap junction of α-tropomyosin on its properties and interaction with actin

International Journal of Biological Macromolecules
A M MatyushenkoAndrey K Tsaturyan

Abstract

Tropomyosin (Tpm) plays a crucial role in the regulation of muscle contraction by controlling actin-myosin interaction. Tpm coiled-coil molecules bind each other via overlap junctions of their N- and C-termini and form a semi-rigid strand that binds the helical surface of an actin filament. The high bending stiffness of the strand is essential for high cooperativity of muscle regulation. Point mutations M8R and K15N in the N-terminal part of the junction and the A277V one in the C-terminal part are associated with dilated cardiomyopathy, while the M281T and I284V mutations are related to hypertrophic cardiomyopathy. To reveal molecular mechanism(s) underlying these pathologies, we studied the properties of recombinant Tpm carrying these mutations using several experimental approaches and molecular dynamic simulation of the junction. The M8R and K15N mutations weakened the interaction between the N- and C-termini of Tpm in the overlap junction and reduced the Tpm affinity for actin. These changes possibly led to a reduction in the regulation cooperativity. The C-terminal mutations caused only small and controversial changes in properties of Tpm and its complex with actin. Their involvement in disease phenotype is possibly caused...Continue Reading

Citations

Sep 20, 2019·Journal of Muscle Research and Cell Motility·Galina V KopylovaAndrey K Tsaturyan
Nov 11, 2019·Diagnostics·Ekaterina M StakhnevaYuliya I Ragino
Oct 24, 2019·Journal of Muscle Research and Cell Motility·Galina V KopylovaSergey Y Bershitsky
Aug 17, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Alexander M MatyushenkoDmitrii I Levitsky
Nov 22, 2020·International Journal of Molecular Sciences·Marina A MarchenkoAlexander M Matyushenko
Oct 7, 2020·The Journal of Biological Chemistry·Alice Ward RaccaJeffrey R Moore
Nov 2, 2020·International Journal of Biological Macromolecules·Victoria V NefedovaDmitrii I Levitsky
Dec 29, 2019·Biophysical Journal·SaiLavanyaa SundarJeffrey R Moore
Jan 18, 2021·The Journal of Biological Chemistry·Alice Ward RaccaJeffrey R Moore
Jun 3, 2021·International Journal of Molecular Sciences·Marina MarchenkoAlexander Matyushenko
Jul 29, 2021·Scientific Reports·Estela Selma-SorianoJosep Redón
Aug 3, 2021·Archives of Biochemistry and Biophysics·Marina A MarchenkoDmitrii I Levitsky

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