Essential “ankle” in the myosin lever arm

Pylypenko, Olena; Houdusse, Anne

doi:10.1073/pnas.1017676108

Cited by 19 publications

(20 citation statements)

References 25 publications

(24 reference statements)

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“…This lever arm model, at least in its simplest form, implies that the LCD is relatively rigid, so that its rotation with respect to the catalytic domain is transferred efficiently to its connection with the myosin filament. However, crystallographic studies of isolated myosin head fragments have provided evidence for flexibility within the LCD (7)(8)(9)(10). In smooth muscle and invertebrate skeletal muscle, changes in LCD conformation associated with internal flexibility are likely to be linked to myosin-based regulation of contraction (11).…”

Section: Introductionmentioning

confidence: 99%

Orientation of the N-Terminal Lobe of the Myosin Regulatory Light Chain in Skeletal Muscle Fibers

Romano

Brandmeier

Sun

et al. 2012

Biophysical Journal

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The orientation of the N-terminal lobe of the myosin regulatory light chain (RLC) in demembranated fibers of rabbit psoas muscle was determined by polarized fluorescence. The native RLC was replaced by a smooth muscle RLC with a bifunctional rhodamine probe attached to its A, B, C, or D helix. Fiber fluorescence data were interpreted using the crystal structure of the head domain of chicken skeletal myosin in the nucleotide-free state. The peak angle between the lever axis of the myosin head and the fiber or actin filament axis was 100-110° in relaxation, isometric contraction, and rigor. In each state the hook helix was at an angle of ∼40° to the lever/filament plane. The in situ orientation of the RLC D and E helices, and by implication of its N- and C-lobes, was similar in smooth and skeletal RLC isoforms. The angle between these two RLC lobes in rigor fibers was different from that in the crystal structure. These results extend previous crystallographic evidence for bending between the two lobes of the RLC to actin-attached myosin heads in muscle fibers, and suggest that such bending may have functional significance in contraction and regulation of vertebrate striated muscle.

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Section: Introductionmentioning

confidence: 99%

Orientation of the N-Terminal Lobe of the Myosin Regulatory Light Chain in Skeletal Muscle Fibers

Romano

Brandmeier

Sun

et al. 2012

Biophysical Journal

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“…As a result, the deformation analysis of the 20 lowest energy modes predicted the hinge region of the TgMyoA lever arm between TgELCs and the converter domain, and an additional hinge between TgELCs and MLC1 (complex 2 in Fig 7C and complex 1 in S6B Fig). Such dynamics of the myosin light chains is similar as previously described in conventional myosins [33, 34] and the flexibility in the first TgMyoA hinge can contribute to the efficient rebinding of the myosin motor domain to actin in the pre-power stroke state (6SC Fig) [35]. In conclusion, the structures of the trimeric complexes composed of the TgMyoA light chains and TgMyoA C-terminus are compatible with the full-length TgMyoA and exhibit dynamics that is similar to the dynamics of conventional myosins.…”

Section: Resultsmentioning

confidence: 54%

“…Finally, essential light chains generally interact with the myosin converter domain and presumably stabilize the hinge of the myosin neck between the ELC and the converter domain (TgMyoA residues 775-777) [34, 35]. A small interaction interface between the converter domain and TgELC1 has also been shown previously [15].…”

Section: Discussionmentioning

confidence: 92%

“…Similarly, to other essential light chains, TgELC1 and TgELC2 bind calcium in their first EF hand by residues just adjacent to the interface with MLC1. The calcium ion is supposed to support the stiffness of the myosin helix kink (TgMyoA residues 801-803) and mediate transfer of the small conformational changes of the distal regulatory light chain upon phosphorylation to the myosin motor domain [35, 43]. Contrary to that, the calcium-free crystal structure of complex 1 displayed an identical conformation, forming an even larger interface with MLC1 than the calcium-bound structure.…”

Section: Discussionmentioning

confidence: 99%

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Structural role of essential light chains in the apicomplexan glideosome

Pažický

Dhamotharan

Kaszuba

et al. 2019

Preprint

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28Apicomplexan parasites, such as Plasmodium falciparum and Toxoplasma gondii, traverse 29 the host tissues and invade the host cells exhibiting a specific type of motility called gliding. 30The molecular mechanism of gliding lies in the actin-myosin motor localized to the 31 intermembrane space between the plasma membrane and inner membrane complex (IMC) of 32 the parasites. Myosin A (MyoA) is a part of the glideosome, a large multi-protein complex, 33 which is anchored in the outer membrane of the IMC. MyoA is bound to the proximal essential 34 light chain (ELC) and distal myosin light chain (MLC1), which further interact with the 35 glideosome associated proteins GAP40, GAP45 and GAP50. Whereas structures of several 36 individual glideosome components and small dimeric complexes have been solved, structural 37 information concerning the interaction of larger glideosome subunits and their role in 38 glideosome function still remains to be elucidated. Here, we present structures of a T. gondii 39 trimeric glideosome sub complex composed of a myosin A light chain domain with bound 40 MLC1 and TgELC1 or TgELC2. Regardless of the differences between the secondary 41 structure content observed for free P. falciparum PfELC and T. gondii TgELC1 or TgELC2, 42 the proteins interact with a conserved region of TgMyoA to form structurally conserved 43 complexes. Upon interaction, the essential light chains undergo contraction and induce 44 α-helical structure in the myosin A C-terminus, stiffening the myosin lever arm. The complex 45 formation is further stabilized through binding of a single calcium ion to T. gondii ELCs. Our 46 work provides an important step towards the structural understanding of the entire glideosome 47 and uncovering the role of its members in parasite motility and invasion. 48 49 50 3 51 Author summary 52 Apicomplexans, such as Toxoplasma gondii or the malaria agent Plasmodium falciparum, are 53 small unicellular parasites that cause serious diseases in humans and other animals. These 54 parasites move and infect the host cells by a unique type of motility called gliding. Gliding is 55 empowered by an actin-myosin molecular motor located at the periphery of the parasites. 56 Myosin interacts with additional proteins such as essential light chains to form the glideosome, 57 a large protein assembly that anchors myosin in the inner membrane complex. Unfortunately, 58 our understanding of the glideosome is insufficient because we lack the necessary structural 59 information. Here we describe the first structures of trimeric glideosome sub complexes of T. 60 gondii myosin A bound to two different light chain combinations, which show that T. gondii and 61 P. falciparum form structurally conserved complexes. With an additional calcium-free complex 62 structure, we demonstrate that calcium binding does not change the formation of the 63 complexes, although it provides them with substantial stability. With additional data, we 64 propose that the role of the essential light chains is to enhance myosin perfor...

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“…Myosin Structure and System Behaviors. The developed analytical model for describing steady-state myosin interactions with a filament traveling at velocity v was informed by the swinging lever arm theory (36,37). Three parameters represent structural differences among isoforms: lever arm length l, chemical attachment rate to a nearby filament binding site k on , and chemical detachment rate when negatively strained k off (38)(39)(40)(41)(42)(43).…”

Section: Resultsmentioning

confidence: 99%

Robust mechanobiological behavior emerges in heterogeneous myosin systems

Egan

Moore

Ehrlicher

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Biological complexity presents challenges for understanding natural phenomenon and engineering new technologies, particularly in systems with molecular heterogeneity. Such complexity is present in myosin motor protein systems, and computational modeling is essential for determining how collective myosin interactions produce emergent system behavior. We develop a computational approach for altering myosin isoform parameters and their collective organization, and support predictions with in vitro experiments of motility assays with α-actinins as molecular force sensors. The computational approach models variations in single myosin molecular structure, system organization, and force stimuli to predict system behavior for filament velocity, energy consumption, and robustness. Robustness is the range of forces where a filament is expected to have continuous velocity and depends on used myosin system energy. Myosin systems are shown to have highly nonlinear behavior across force conditions that may be exploited at a systems level by combining slow and fast myosin isoforms heterogeneously. Results suggest some heterogeneous systems have lower energy use near stall conditions and greater energy consumption when unloaded, therefore promoting robustness. These heterogeneous system capabilities are unique in comparison with homogenous systems and potentially advantageous for high performance bionanotechnologies. Findings open doors at the intersections of mechanics and biology, particularly for understanding and treating myosin-related diseases and developing approaches for motor molecule-based technologies.

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Essential “ankle” in the myosin lever arm

Cited by 19 publications

References 25 publications

Orientation of the N-Terminal Lobe of the Myosin Regulatory Light Chain in Skeletal Muscle Fibers

Orientation of the N-Terminal Lobe of the Myosin Regulatory Light Chain in Skeletal Muscle Fibers

Structural role of essential light chains in the apicomplexan glideosome

Robust mechanobiological behavior emerges in heterogeneous myosin systems

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