Structural basis for calcium-regulated relaxation of striated muscles at interaction sites of troponin with actin and tropomyosin.
In summary, we have shown that the TnI-TnC-TnT2 ternary complex (-52 kDa) has a mobile actin-binding domain (-6.1 kDa) that tumbles independently of the core domain. By docking the mobile domain and the core domain into the cryo-EM map obtained for thin filaments at low Ca2+, a model for actin-troponin interaction has been obtained. This model shows the atomic details of interactions of actin with the mobile domain and suggests the mechanism by which troponin generates a shift in the azimuthal position of tropomyosin in response to changes in Ca2+ levels. In this model the mobile domain of troponin interacts with three actins and one troponin interacts with four actin molecules. The relationship between myosin and the mobile domain suggests that the latter may work as a fail-safe latch to secure a relaxed state. The model also provides insights into many mutations associated with human cardiomyopathy and has implications for the function of other actin-binding proteins. Coordinates of the mobile domain have been deposited in the Protein Data Bank under accession codes 1VDI (low Ca2+) and 1VDJ (high Ca2+). Chemical shifts of the mobile domain have been deposited in the BMRB under accession ID 18140.
Murakami
Kenji
K
Department of Biosciences, School of Science and Engineering, Teikyo University, Toyosatodai 1-1, Utsunomiya 320-8551, Japan.
Yumoto
Fumiaki
F
Ohki
Shin-Ya
SY
Yasunaga
Takuo
T
Tanokura
Masaru
M
Wakabayashi
Takeyuki
T
D000199:Actins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D018360:Crystallography, X-Ray; D006801:Humans; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D014335:Tropomyosin / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D014336:Troponin / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology
D000199:Actins; D014335:Tropomyosin; D014336:Troponin; D002118:Calcium