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Structural basis for Ca2+-regulated muscle relaxation at interaction sites of troponin with actin and tropomyosin.

Murakami K, Yumoto F, Ohki SY, Yasunaga T, Tanokura M, Wakabayashi T
J Mol Biol 352 178-201 (2005)
Cited: 83 times
EuropePMC logo PMID: 16061251

Abstract

Troponin and tropomyosin on actin filaments constitute a Ca2+-sensitive switch that regulates the contraction of vertebrate striated muscle through a series of conformational changes within the actin-based thin filament. Troponin consists of three subunits: an inhibitory subunit (TnI), a Ca2+-binding subunit (TnC), and a tropomyosin-binding subunit (TnT). Ca2+-binding to TnC is believed to weaken interactions between troponin and actin, and triggers a large conformational change of the troponin complex. However, the atomic details of the actin-binding sites of troponin have not been determined. Ternary troponin complexes have been reconstituted from recombinant chicken skeletal TnI, TnC, and TnT2 (the C-terminal region of TnT), among which only TnI was uniformly labelled with 15N and/or 13C. By applying NMR spectroscopy, the solution structures of a "mobile" actin-binding domain (approximately 6.1 kDa) in the troponin ternary complex (approximately 52 kDa) were determined. The mobile domain appears to tumble independently of the core domain of troponin. Ca2+-induced changes in the chemical shift and line shape suggested that its tumbling was more restricted at high Ca2+ concentrations. The atomic details of interactions between actin and the mobile domain of troponin were defined by docking the mobile domain into the cryo-electron microscopy (cryo-EM) density map of thin filament at low [Ca2+]. This allowed the determination of the 3D position of residue 133 of TnI, which has been an important landmark to incorporate the available information. This enabled unique docking of the entire globular head region of troponin into the thin filament cryo-EM map at a low Ca2+ concentration. The resultant atomic model suggests that troponin interacted electrostatically with actin and caused the shift of tropomyosin to achieve muscle relaxation. An important feature is that the coiled-coil region of troponin pushed tropomyosin at a low Ca2+ concentration. Moreover, the relationship between myosin and the mobile domain on actin filaments suggests that the latter works as a fail-safe latch.

Reviews - 1vdi mentioned but not cited (1)

  1. Structural basis for calcium-regulated relaxation of striated muscles at interaction sites of troponin with actin and tropomyosin. Murakami K, Yumoto F, Ohki SY, Yasunaga T, Tanokura M, Wakabayashi T. Adv Exp Med Biol 592 71-86 (2007)

Articles - 1vdi mentioned but not cited (2)

  1. Distal arthrogryposis with variable clinical expression caused by TNNI2 mutation. Čulić V, Miyake N, Janković S, Petrović D, Šimunović M, Đapić T, Shiina M, Ogata K, Matsumoto N. Hum Genome Var 3 16035 (2016)
  2. The muscle-relaxing C-terminal peptide from troponin I populates a nascent helix, facilitating binding to tropomyosin with a potent therapeutic effect. Hornos F, Feng HZ, Rizzuti B, Palomino-Schätzlein M, Wieczorek D, Neira JL, Jin JP. J Biol Chem 296 100228 (2021)


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