Muscle myosin filaments: cores, crowns and couplings

Abstract

Myosin filaments in muscle, carrying the ATPase myosin heads that interact with actin filaments to produce force and movement, come in multiple varieties depending on species and functional need, but most are based on a common structural theme. The now successful journeys to solve the ultrastructures of many of these myosin filaments, at least at modest resolution, have not been without their false starts and erroneous sidetracks, but the picture now emerging is of both diversity in the rotational symmetries of different filaments and a degree of commonality in the way the myosin heads are organised in resting muscle. Some of the remaining differences may be associated with how the muscle is regulated. Several proteins in cardiac muscle myosin filaments can carry mutations associated with heart disease, so the elucidation of myosin filament structure to understand the effects of these mutations has a clear and topical clinical relevance.

Lessons from a tarantula: new insights into muscle thick filament and myosin interacting-heads motif structure and function

“…In 2005, Squire conceptualized four Classes of configurations for myosin heads organization on the relaxed thick filament surface according to how the head-tohead interactions stabilized the helical structures in resting muscle: in Class I, the two heads of one myosin molecule might interact with each other in a parallel fashion; in Class II the two heads might separate laterally and interact with a head from an adjacent myosin molecule in the same crown; in Class III the two heads might separate in an antiparallel or splayed way with heads of successive crowns making interactions between them; and in Class IV the heads do not interact with each other at all (Squire et al 2005;Squire 2009). …”

“…4c1-4) were ambiguous since at a 5-nm resolution the fitting did not allowed resolving the densities of both heads which were assumed to be identical. The suggested arrangement, in which the heads between adjacent crowns interacts between them along the long-pitched helices, is called the BClass III^model (Squire et al 2005;Squire 2009). Therefore, by the year 2000, the tarantula thick filaments were thought to be of Class III although a higher resolution than 5.0 nm was required for an unambiguous fitting.…”

“…4 For the elucidation of the tarantula thick filament structure three requisites were needed to be fulfilled: a a better resolution of 3D reconstructions from negatively stained isolated filaments (a1-4 resolution 5.0 nm) or frozen-hydrated (a5 2.5 nm, a6 2.0 nm and a7 1.3 nm) with enhanced 3D reconstruction and visualization techniques (HR helical reconstruction, IHRSR iterative helical real space reconstruction), b the myosin head structure (b2) (PDB MYS1) and improved two-heads (b3-7) models and (c) fitting approaches ranging from eye-fitting (c1), 2D fitting (c2), envelope 3D fitting (c3), density rigid 3D fitting (c4, 5) and flexible 3D fitting (c6, 7). The unambiguous interpretation that lead to the myosin interacting-heads motif (IHM) (Woodhead et al 2005) (a5, red circle) in the relaxed tarantula thick filament, belonging to the Class I proposed by Squire et al (2005) and Squire (2009), required a resolution higher that 2.5 nm achieved by the IHRSR technique, frozen-hydrated specimens (a5) and an asymmetric head-pair model (b4) (Wendt et al 2001), but with the S2 properly positioned (b5). In retrospect, the motif (red circles) was present and could be picked out on the 5-nm resolution 3D maps using the right density cutoffs (yellow circles).…”

“…1b) (Huxley and Brown 1967). This model inspired Huxley's seminal ideas on the mechanism of muscular contraction, which he called the swinging, tilting crossbridge-sliding filament mechanism (Huxley 1969(Huxley , 2004b and started the analysis of thick filament structure and function (reviewed by Squire 1975Squire , 1981Squire , 1986Squire , 2009Barral and Epstein 1999;Craig and Padrón 2004;Squire et al 2005;Hooper and Thuma 2005;Craig and Woodhead 2006;Hooper et al 2008;AL-Khayat 2013;Vandenboom 2017).…”

Atomic model of the human cardiac muscle myosin filament

“…Within the C zone, the titin domains are distributed in a pattern corresponding to an 11-domain superrepeat every 429 Å. The cardiac isoform of MyBP-C (cMyBP-C) has a mass of ∼140 kDa and is made up of a linear array of 11 Ig and Fn3 domains.Myosin filament structure has been investigated both by electron microscopy and by X-ray fiber diffraction to explore the different organizations and properties of myosin filaments from a variety of organisms and tissues (7,8). The most detailed structural description of a myosin filament (to date) derives from helical 3D reconstruction of cryoelectron microscope images of tarantula myosin filaments at a resolution of ∼25 Å (9, 10).…”