Lessons from a tarantula: new insights into myosin interacting-heads motif evolution and its implications on disease

Álamo, Lorenzo; Pinto, Antonio; Sulbarán, Guidenn; Mavárez, Jesús; Padrón, Raúl

doi:10.1007/s12551-017-0292-4

Cited by 44 publications

(53 citation statements)

References 84 publications

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“…Thus, BS binding is compatible with the sequestered state. The fact that BS favors the off state 40 is a strong argument in favor of the model previously proposed 41 from low resolution EM maps which we have defined at a better resolution here with both heads mainly unaffected for the motor domain but which uses hinges at the converter/ELC interface to allow the asymmetric association of the myosin heads to form the IHM (Fig. 6).…”

Section: Implications For Future Treatmentsmentioning

confidence: 73%

Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition

Robert-Paganin

Auguin²,

Houdusse³

2018

Preprint

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Abstract:Hypertrophic cardiomyopathies (HCM) result from distinct single-point mutations in sarcomeric proteins that lead to muscle hypercontractility. While different models account for a pathological increase in the power output, clear understanding of the molecular basis of dysfunction in HCM is the mandatory next step to improve current treatments. An optimized quasi-atomic model of the sequestered state of cardiac myosin coupled to X-ray crystallography and in silico analysis of the mechanical compliance of the lever arm allowed us to perform a systematic study for a large set of HCM mutations. We define different classes of mutations depending on their effects on lever arm compliance, sequestered state stability and motor functions. This work reconciles previous models and explains how distinct HCM mutations can have disparate effects on the motor mechano-chemical parameters and yet lead to the same disease. The framework presented here can guide future investigations aiming at finding HCM treatments.

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Section: Implications For Future Treatmentsmentioning

confidence: 73%

Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition

Robert-Paganin

Auguin²,

Houdusse³

2018

Preprint

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“…A second cautionary note is that while purified smooth muscle HMM has been shown to form an IHM structure by high-resolution electron microscopy [ 96 , 97 ], most studies related to the IHM structure are based on low-resolution (≥ 2 nm) EM reconstructions from isolated myosin thick filaments (for reviews, see [ 6 , 88 ]). It is imperative that the high-resolution structure of the folded-back sequestered state of human β-cardiac myosin be determined.…”

Section: The Second Perspective: Hypercontractility Results From An Imentioning

confidence: 99%

Three perspectives on the molecular basis of hypercontractility caused by hypertrophic cardiomyopathy mutations

Spudich

2019

Pflugers Arch - Eur J Physiol

139

156

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Several lines of evidence suggest that the primary effect of hypertrophic cardiomyopathy mutations in human β-cardiac myosin is hypercontractility of the heart, which leads to subsequent hypertrophy, fibrosis, and myofilament disarray. Here, I describe three perspectives on the molecular basis of this hypercontractility. The first is that hypercontractility results from changes in the fundamental parameters of the actin-activated β-cardiac myosin chemo-mechanical ATPase cycle. The second considers that hypercontractility results from an increase in the number of functionally accessible heads in the sarcomere for interaction with actin. The final and third perspective is that load dependence of contractility is affected by cardiomyopathy mutations and small-molecule effectors in a manner that changes the power output of cardiac contraction. Experimental approaches associated with each perspective are described along with concepts of therapeutic approaches that could prove valuable in treating hypertrophic cardiomyopathy.

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“…This single molecular entity found in tarantula thick filaments was called the myosin interactingheads motif (IHM) (Alamo et al 2008) and its consequences on structure and function are the focus of this review. We review the IHM evolution and its implications on disease in Alamo et al (2017a).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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The tarantula skeletal muscle X-ray diffraction pattern suggested that the myosin heads were helically arranged on the thick filaments. Electron microscopy (EM) of negatively stained relaxed tarantula thick filaments revealed four helices of heads allowing a helical 3D reconstruction. Due to its low resolution (5.0 nm), the unambiguous interpretation of densities of both heads was not possible. A resolution increase up to 2.5 nm, achieved by cryo-EM of frozen-hydrated relaxed thick filaments and an iterative helical real space reconstruction, allowed the resolving of both heads. The two heads, Bfree^and Bblocked^, formed an asymmetric structure named the Binteracting-heads motif^(IHM) which explained relaxation by self-inhibition of both heads ATPases. This finding made tarantula an exemplar system for thick filament structure and function studies. Heads were shown to be released and disordered by Ca 2+ -activation through myosin regulatory light chain phosphorylation, leading to EM, small angle X-ray diffraction and scattering, and spectroscopic and biochemical studies of the IHM structure and function. The results from these studies have consequent implications for understanding and explaining myosin super-relaxed state and thick filament activation and regulation. A cooperative phosphorylation mechanism for activation in tarantula skeletal muscle, involving swaying constitutively Ser35 mono-phosphorylated free heads, explains super-relaxation, force potentiation and posttetanic potentiation through Ser45 mono-phosphorylated blocked heads. Based on this mechanism, we propose a swaying-swinging, tilting crossbridge-sliding filament for tarantula muscle contraction.

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Lessons from a tarantula: new insights into myosin interacting-heads motif evolution and its implications on disease

Cited by 44 publications

References 84 publications

Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition

Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition

Three perspectives on the molecular basis of hypercontractility caused by hypertrophic cardiomyopathy mutations

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

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