Andrey Tsaturyan

Tel Aviv University | TAU · Department of Physiology and Pharmacology

We characterized a novel genetic variant c.292G > A (p.E98K) in the TPM1 gene encoding cardiac tropomyosin 1.1 isoform (Tpm1.1), found in a proband with a phenotype of complex cardiomyopathy with conduction dysfunction and slow progressive neuromuscular involvement. To understand the molecular mechanism by which this mutation impairs cardiac functi...

In the myocardium, the TPM1 gene expresses two isoforms of tropomyosin (Tpm), alpha (αTpm; Tpm 1.1) and kappa (κTpm; Tpm 1.2). κTpm is the result of alternative splicing of the TPM1 gene. We studied the structural features of κTpm and its regulatory function in the atrial and ventricular myocardium using an in vitro motility assay. We tested the po...

The propagation of the membrane tension perturbations is a, potentially, essential mechanism of the mechanical signal transduction along surfaces of live cells. The efficiency of this process is determined by the propagation speed, which turned to be a hot and a controversial topic of the Cell Biophysics. In a stark contrast to the earlier results...

Contraction of cardiac muscle is regulated by Ca2+ ions via regulatory proteins, troponin (Tn), and tropomyosin (Tpm) associated with the thin (actin) filaments in myocardial sarcomeres. The binding of Ca2+ to a Tn subunit causes mechanical and structural changes in the multiprotein regulatory complex. Recent cryo-electron microscopy (cryo-EM) mode...

The effect of mechano-electrical feedback on re-entry formation and maintenance was studied using a model of myocardial electromechanics that accounts for two components of myocardial conductivity and delayed strain-dependent changes in membrane capacitance that causes a conduction slowing. Two scenarios were simulated in 2D numerical experiments:...

Hypertrophic cardiomyopathy (HCM), caused by mutations in thin filament proteins, manifests as moderate cardiac hypertrophy and is associated with sudden cardiac death (SCD). We identified a new de novo variant, c.656A>T (p.D219V), in the TPM1 gene encoding cardiac tropomyosin 1.1 (Tpm) in a young SCD victim with post-mortem-diagnosed HCM. We produ...

Electron microscopy shows that myosin heads in thick filaments isolated from striated muscles interact with each other and with the myosin tail under relaxing conditions. This “interacting-heads motif” (IHM) is highly conserved across the animal kingdom and is thought to be the basis of the super-relaxed state. However, a recent X-ray modeling stud...

A model of myocardial electromechanics is suggested. It combines modified and simplified versions of previously published models of cardiac electrophysiology, excitation-contraction coupling, and mechanics. The mechano-calcium and mechano-electrical feedbacks, including the strain-dependence of the propagation velocity of the action potential, are...

Kozlovskaya et al. [1] and Grigoriev et al. [2] showed that enormous loss of muscle stiffness (atonia) develops in humans under true (space flight) and simulated microgravity conditions as early as after the first days of exposure. This phenomenon is attributed to the inactivation of slow motor units and called reflectory atonia. However, a lot of...

The temperature dependences of the tension and stiffness of actively contracting single fibers of the rabbit slow muscle (m. soleus) were studied using the Joule temperature jump. Differences in the characteristics of the fibers of the rabbit fast (m. psoas) and slow (m. soleus) muscles were shown; apparently, they were caused by differences in the...

Tropomyosin (Tpm) is an actin-binding protein that plays a crucial role in the regulation of muscle contraction. Numerous point mutations in the TPM3 gene encoding Tpm of slow skeletal muscles (Tpm 3.12 or γ-Tpm) are associated with the genesis of various congenital myopathies. Two of these mutations, R91P and R245G, are associated with congenital...

Tropomyosin (Tpm) is one of the major actin-binding proteins that play a crucial role in the regulation of muscle contraction. The flexibility of the Tpm molecule is believed to be vital for its functioning, although its role and significance are under discussion. We choose two sites of the Tpm molecule that presumably have high flexibility and sta...

We applied various methods to investigate how mutations S283D and S61D that mimic phosphorylation of tropomyosin (Tpm) affect structural and functional properties of cardiac Tpm carrying cardiomyopathy-associated mutations in different parts of its molecule. Using differential scanning calorimetry and molecular dynamics, we have shown that the S61D...

The effects of two cardiomyopathy-associated mutations in regulatory sarcomere protein tropomyosin (Tpm) on heart function were studied with a new multiscale model of the cardiovascular system (CVS). They were a Tpm mutation, Ile284Val, associated with hypertrophic cardiomyopathy (HCM), and an Asp230Asn one associated with dilated cardiomyopathy (D...

Striated muscle contraction involves sliding of actin thin filaments along myosin thick filaments, controlled by calcium through thin filament activation. In relaxed muscle, the two heads of myosin interact with each other on the filament surface to form the interacting-heads motif (IHM). A key question is how both heads are released from the surfa...

Tropomyosin is a dimer coiled-coil actin-binding protein. Adjacent tropomyosin molecules connect each other ‘head-to-tail’ via an overlap junction and form a continuous strand that winds around an actin filament and controls the actin–myosin interaction. High cooperativity of muscle contraction largely depends on tropomyosin characteristics. Here w...

A multiscale model of the cardiovascular system (CVS) in which the left ventricle (LV) of the heart was approximated by an axisymmetrical thick-wall body made of transversely isotropic incompressible material was used to simulate the performance of the heart with apical myocardial infarction (MI). The material model reproduced mechanical properties...

A new mathematical model of the cardiovascular system is proposed. The left ventricle is described by an axisymmetric multiscale model where myocardium is treated as an incompressible transversely isotropic medium with a realistic distribution of fibre orientation. Active tension and its regulation by Ca2+ ions are described by our recent kinetic m...

Tropomyosin (Tpm) is a coiled-coil actin-binding dimer protein that participates in the regulation of muscle contraction. Both Tpm chains contain Cys190 residues which are normally in the reduced state, but form an interchain disulfide bond in failing heart. Changes in structural and functional properties of Tpm and its complexes with actin upon di...

Tropomyosin (Tpm) plays a crucial role in the regulation of muscle contraction by controlling actin-myosin interaction. Tpm coiled-coil molecules bind each other via overlap junctions of their N- and C-termini and form a semi-rigid strand that binds the helical surface of an actin filament. The high bending stiffness of the strand is essential for...

The study was aimed at testing the hypotheses about the role of cross-bridges and calpains in reduction of rat soleus passive tension under conditions of hindlimb unloading. For this purpose, we used an inhibitor of μ-calpain PD 150606 as well as a blocker of actomyosin interaction (blebbistatin). It was found for the first time that a decrease in...

We studied the effect of the replacement of two highly conserved noncanonical residues in the α-chain of tropomyosin, that is, Asp137 and Gly126, with the canonical residues, Leu and Arg, on the mechanical properties of reconstructed thin filaments that contain αβ-heterodimers of tropomyosin. For this purpose, the reconstructed thin filaments that...

Tropomyosin (Tpm) is an α-helical coiled-coil actin-binding protein playing an essential role in the regulation of muscle contraction. The middle part of the Tpm molecule has some specific features, such as the presence of non-canonical residues as well as a substantial gap at the interhelical interface, which are believed to destabilize coiled-coi...

An axisymmetric model is suggested to simulate mechanical performance of the left ventricle of the heart. Cardiac muscle is treated as incompressible anisotropic material with active tension directed along muscle fibres. This tension depends on kinetic variables that characterize interaction of contractile proteins and regulation of muscle contract...

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 interpretati...

Muscle contraction is powered by actin-myosin interaction controlled by Ca²⁺ via the regulatory proteins troponin (Tn) and tropomyosin (Tpm), which are associated with actin filaments. Tpm forms coiled-coil dimers, which assemble into a helical strand that runs along the whole ∼1 μm length of a thin filament. In the absence of Ca²⁺, Tn that is tigh...

Muscle contraction is powered by myosin interaction with actin-based thin filaments containing Ca(2+)-regulatory proteins, tropomyosin and troponin. Coiled-coil tropomyosin molecules form a long helical strand that winds around actin filament and either shields actin from myosin binding or opens it. Non-canonical residues G126 and D137 in the centr...

A simple model of cardiac muscle was designed for multiscale simulation of heart mechanics. Relaxed cardiac muscle was described as a transversally isotropic hyperelastic material. Active tension caused by actin-myosin crossbridges depends on the ensemble averaged strain of myosin heads bound to actin. Calcium activation was modeled by Ca(2+) bindi...

Contraction of skeletal and cardiac muscle is controlled by Ca2+ ions via regulatory proteins, troponin (Tn) and tropomyosin (Tpm) associated with the thin actin filaments in sarcomeres. In the absence of Ca2+, Tn-C binds actin and shifts the Tpm strand to a position where it blocks myosin binding to actin, keeping muscle relaxed. According to the...

Myocardial heterogeneity is well appreciated and widely documented, from sub-cellular to organ levels. This paper reviews significant achievements of the group, led by Professor Vladimir S. Markhasin, Russia, who was one of the pioneers in studying and interpreting the relevance of cardiac functional heterogeneity.

Results of the numerical simulation of the end-diastolic, end-systolic, and stroke volumes of the left ventricle of the heart are presented. The simulation was based on a published simple kinetic model of cardiac muscle and approximation of the ventricle geometry with thick-wall cylinder where the fiber orientation varied linearly from sub-epicardi...

A two-beam optical trap was used to measure the bending stiffness of F-actin and reconstructed thin filaments. A dumbbell was formed by a filament segment attached to two beads that were held in the two optical traps. One trap was static and held a bead used as a force transducer, whereas an acoustooptical deflector moved the beam holding the secon...

During eccentric contraction, muscle is lengthening so that the actin-myosin cross-bridges bear a load that exceeds the force they generate during isometric contraction. Using the optical trap technique, we simulated eccentric contraction at the single molecule level and investigated the effect of load on the skeletal actomyosin lifetime at differe...

An axisymmetric model is suggested to simulate mechanical performance of the left ventricle of the heart. Cardiac muscle is treated as incompressible anisotropic material with active tension directed along muscle fibres. This tension depends on kinetic variables that characterize interaction of contractile proteins and regulation of muscle contract...

Tropomyosin (Tm) is an α-helical coiled-coil protein that binds along the length of actin filament and plays an essential role in the regulation of muscle contraction. There are two highly conserved non-canonical residues in the middle part of the Tm molecule, Asp137 and Gly126, which are thought to impart conformational instability (flexibility) t...

Apart from fast, efficient and coordinated contraction of several skeletal muscles, running and jumping require effective absorption of the kinetic energy of the body during the landing phase, to absorb impact forces and prevent injury. This is done not only by joints, bones and tendons, but also by activated muscles which resist stretch. During le...

Skeletal muscles power body movement by converting free energy of ATP hydrolysis into mechanical work. During the landing phase of running or jumping some activated skeletal muscles are subjected to stretch. Upon stretch they absorb body energy quickly and effectively thus protecting joints and bones from impact damage. This is achieved because dur...

We show that the mutations D137L and G126R, which stabilize the central part of the tropomyosin (Tm) molecule, increase both the maximal sliding velocity of the regulated actin filaments in the in vitro motility assay at high Са2+ concentrations and the Са2+-sensitivity of the actin-myosin interaction underlying this sliding. Based on an analysis o...

We present a model of Ca-regulated thin filaments in cardiac muscle where tropomyosin is treated as a continuous elastic chain confined in the closed position on the actin helix by electrostatic forces. The main distinction from previous works is that the intrinsic stress-free helical shape of the tropomyosin chain was taken into account explicitly...

We show that the mutations D137L and G126R, which stabilize the central part of the tropomyosin (Tm) molecule, increase both the maximal sliding velocity of the regulated actin filaments in the in vitro motility assay at high Ca2+ concentrations and the Ca2+-sensitivity of the actin-myosin interaction underlying this sliding. Based on an analysis o...

A simple kinetic model of muscle contraction is suggested. The rates of cross-bridge transitions from one kinetic state to another are supposed to depend on the averaged (over ensemble of actin-bound bridges) strain. With a proper set of the strain-dependent rates the model fits well a broad set of experimental data. Due to its simplicity, the rela...

A simple kinetic model of muscle contraction is suggested. The rates of cross-bridge transitions from one kinetic state to another one are supposed to depend on the strain averaged over an ensemble of actin-bound bridges. With a proper set of strain-dependent rate constants, the model fits well a broad range of experimental data. Owing to that the...

The interaction of actin and myosin powers striated and smooth muscles and some other types of cell motility. Due to its highly ordered structure, skeletal muscle is a very convenient object for studying the general mechanism of the actin-myosin molecular motor. The history of investigation of the actin-myosin motor is briefly described. Modern con...

A mathematical model of sarcomere mechanics, which takes into account the elongation of actin and myosin filaments and also twisting of the actin filaments in the sarcomere of striated muscle during contraction is presented. The model accounts for the experimentally observed phenomena of the stretch and twist of the actin filaments due to strong bi...

The duty ratio, or the part of the working cycle in which a myosin molecule is strongly attached to actin, determines motor processivity and is required to evaluate the force generated by each molecule. In muscle, it is equal to the fraction of myosin heads that are strongly, or stereospecifically, bound to the thin filaments. Estimates of this fra...

The duty ratio, or the part of the working cycle in which a myosin molecule is strongly attached to actin, determines motor processivity and is required to evaluate the force generated by each molecule. In muscle, it is equal to the fraction of myosin heads that are strongly, or stereospecifically, bound to the thin filaments. Estimates of this fra...

A mathematical model of the propagation of acoustic shear waves in muscle tissue is considered. The muscle is modelled by an incompressible transversely isotropic viscoelastic continuum with quasi-one-dimensional active tension. Two types of shear waves in an infinite medium have been established. The waves of the second type (transverse) propagate...

Raising the temperature of rabbit skeletal muscle from ∼0°C to ∼20°C has been shown to enhance the helical organization of the myosin heads and to change the intensities of the 10 and 11 equatorial reflections. We show here by time-resolved x-ray diffraction combined with temperature jump that the movement of the heads to enhance the organized myos...

Raising the temperature of rabbit skeletal muscle from ~0 C to ~20 C has been shown to enhance the helical organization of the myosin heads and to change the intensities of the 10 and 11 equatorial reflections. We show here by time-resolved x-ray diffraction combined with temperature jump that the movement of the heads to enhance the organized myos...

A model of sarcomere mechanics, which takes into account the elongation of the actin and myosin filaments and twisting of the actin filaments during muscle contraction is suggested. The model accounts for the experimentally observed phenomena of the stretch and twist of actin filaments due to strong binding of myosin heads and pulling force. Some m...

In sarcomeres of striated muscles the middle parts of adjacent thick filaments are connected to each other by the M-band proteins. To understand the role of the M-band in sarcomere mechanics a model of forces which pull a thick filament to opposite Z-disks of a sarcomere is considered. Forces of actin-myosin cross-bridges, I-band titin segments and...

A structural and kinetic model of actomyosin interaction in a contracting muscle fiber has been proposed, based on the assumption that the myosin molecular motor generates force in two steps. Initially, a nonstereospecifically attached myosin head rolls on the actin surface and stereospecifically locks on actin. Then its α-helical lever arm (neck d...

The interference fine structure of the M3 reflection in the low-angle X-ray diffraction patterns of muscle fibers is used for the measurements of axial movements of myosin heads with a precision of 0.1–0.2 nm. We have measured changes in the M3 interference profile during tension rise induced by a 5°C to 30°C temperature jump in thin bundles of con...

A structural and kinetic model of actomyosin interaction in a contracting muscle fibre has been proposed, which is based on the assumption that the myosin molecular motor generates the force in two steps. Initially the nonstereospecifically attached myosin head rolls at the actin surface and stereospecifically locks on actin. Then the alpha-helical...

The origin of reflections in the x-ray diffraction pattern from striated muscle and their use for understanding the structural organization of the contractile machinery are presented and discussed. Results of x-ray diffraction experiments obtained by a number of research groups using a variety of protocols revealed structural changes in contracting...

TABLE OF CONTENTS 1. Abstract 2. Introduction 3. X-ray diffraction patterns from muscle 3.1. Equatorial reflections 3.2. Meridional reflections 3.2.1. Thin filament reflections 3.2.2. Thick filament reflections 3.3. Layer lines 3.3.1. Myosin layer lines 3.3.2. Actin layer lines 3.3.3. Beating actin-myosin layer lines 4. Time-resolved x-ray diffract...

A direct modeling approach was used to quantitatively interpret the two-dimensional x-ray diffraction patterns obtained from contracting mammalian skeletal muscle. The dependence of the calculated layer line intensities on the number of myosin heads bound to the thin filaments, on the conformation of these heads and on their mode of attachment to a...

Myosin interacts with actin during its enzymatic cycle, and actin stimulates myosin's ATPase activity. There are extensive interaction surfaces on both actin and myosin. Several surface loops of myosin play different roles in actomyosin interaction. However, the functional role of loop 4 in actin binding is still ambiguous. We explored the role of...

The structure of the tightly bound complex of the globular myosin head with F-actin is the key to understanding important details of the mechanism of how the actin-myosin motor functions. The current notion on this complex is based on the docking of known atomic structures of constituent proteins into low-resolution electron-density maps. The atomi...

The structure of the strongly bound complex of the globular myosin head and F-actin is a key for understanding some important details of the mechanism of the actin-myosin motor. Current knowledge about the structure is based on the docking of known atomic structures of actin and myosin heads into low-resolution EM electron density maps. To refine t...

Calculation of the size of the power stroke of the myosin motor in contracting muscle requires knowledge of the compliance of the myofilaments. Current estimates of actin compliance vary significantly introducing uncertainty in the mechanical parameters of the motor. Using x-ray diffraction on small bundles of permeabilized fibers from rabbit muscl...

Muscle force results from the interaction of the globular heads of myosin-II with actin filaments. We studied the structure-function relationship in the myosin motor in contracting muscle fibers by using temperature jumps or length steps combined with time-resolved, low-angle X-ray diffraction. Both perturbations induced simultaneous changes in the...

Available high-resolution structures of F-actin, myosin subfragment 1 (S1), and their complex, actin-S1, were used to calculate a 2D x-ray diffraction pattern from skeletal muscle in rigor. Actin sites occupied by myosin heads were chosen using a "principle of minimal elastic distortion energy" so that the 3D actin labeling pattern in the A-band of...

We describe a procedure whereby structural changes that occur in muscle fibres after a rapid temperature jump can be captured by cryofixation. In the thick filament from rabbit and other mammalian skeletal muscles there is a rapid transition from a non-helical to a helical structure as the temperature is raised from 273 K towards physiological leve...

An expression for cylindrically averaged intensity diffracted by a partially occupied helix (i.e. by a set of identical molecules bound to some, but not all, points of a discrete helix) is derived. The result is compared with previous studies and its application to muscle diffraction is discussed.

Single chemically permeabilized fibres from rabbit psoas muscle were activated maximally at 5-6 degrees C and then exposed to a rapid temperature increase ('T-jump') up to 37 degrees C by passing a high-voltage pulse (40 kHz AC, 0.15 ms duration) through the fibre length. Fibre cooling after the T-jump was compensated by applying a warming (40 kHz...

We describe a procedure whereby structural changes that occur in muscle fibres after a rapid temperature jump can be captured by cryofixation. In the thick filament from rabbit and other mammalian skeletal muscles there is a rapid transition from a non-helical to a helical structure as the temperature is raised from 273 K towards physiological leve...

1. Structural changes following the photolytic release of ATP were observed in single, permeabilised fibres of frog skeletal muscle at 5-6 C, using time-resolved, low-angle X-ray diffraction. The structural order in the fibres and their isometric function were preserved by cross-linking 10-20 % of the myosin cross-bridges to the thin filaments. 2....

by time-resolved X-ray diffraction Structural responses to the photolytic release of ATP in frog muscle fibres, observed This information is current as of September 11, 2007 publication unless article is open access. This version of the article may not be posted on a public website for 12 months after publication. No part of this article may be rep...