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Search Results to Roger W Craig PhD

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overview

Molecular Structure, Dynamics, and Contractile Mechanism of Muscle

We use state-of-the-art electron microscopic techniques to understand how muscles contract. By studying the molecular structures of the actin and myosin filaments, whose interaction is responsible for contraction, we can elucidate the molecular mechanism of force generation and the processes responsible for regulating contraction. We are investigating systems as diverse as the rapidly contracting striated muscles of the skeleton and heart, and the smooth muscles of the internal organs (e.g. blood vessels), which are specialized to contract slowly and to maintain tension over long periods of time. These studies are adding to our basic understanding of muscle function, and also providing a structural basis for understanding muscle diseases caused by malfunction in the actin or myosin filaments.

Techniques: high resolution electron microscopy, 3D reconstruction, and atomic fitting

To decipher these filament structures in three dimensions at the molecular level, we use high resolution electron microscopy combined with computer image reconstruction. Specimens are observed by negative staining or cryo-electron microscopy, and 3D reconstructions of filaments are computed using helical or single particle methods. Atomic level detail is achieved by computationally 'fitting' atomic structures of filament subunits into the reconstruction. To study dynamic changes in filament structure that occur in active muscle, we have developed methods for capturing transient structural intermediates on the millisecond time scale for observation by EM.

Myosin filaments

Using these approaches we have recently achieved a major breakthrough in defining the 3D configuration of the key energy-transducing molecules, the myosin heads, on the surface of striated muscle myosin filaments (Woodhead et al., 2005). These results show for the first time, and in atomic detail, how myosin molecules are switched 'off', bringing about relaxation of muscle. The results suggest that the structure we observe is common to muscles of animals throughout most of the animal kingdom, and they provide a basis for understanding how these filaments are activated in contracting muscle. Our results also reveal for the first time how the tails of the myosin molecules are packed into the backbone of the thick filament, forming small 'subfilaments' that themselves assemble to form the thick filament core. This provides key background information for understanding how myosin filaments assemble in the cell.

Actin filaments

We have also made the first direct observations of how the protein tropomyosin, on the actin filament, regulates contraction by sterically blocking sites of myosin head attachment on actin filaments (Lehman et al., 1994; Xu et al., 1999; Pirani et al., 2005). We are currently determining the organization of the Ca2+-sensitive regulatory complex, troponin, on the thin filament, and how this changes on Ca2+ activation. These studies are revealing in atomic detail the molecular dynamics regulating muscle contraction.

Smooth muscle

In addition to our work on striated muscle, we have also shown that the myosin filaments of smooth muscle have a unique 'side-polar' structure, different from the helical organization in striated muscle. This structure helps to explain the characteristic ability of smooth muscles to undergo high degrees of shortening (Xu et al., 1996). Actin filaments from smooth muscle also differ from those in striated muscle, and we have gained new insights into their functioning in terms of the organization of their associated regulatory proteins (Hodgkinson et al., 1997; Lehman et al., 1997).

Current studies

We are currently determining the head organization in striated muscle myosin filaments from several key organisms, to test the generality of our model of the off state, and to determine whether subfilaments are a common feature of different species. We are imaging filaments at higher resolution to determine further details of their structure, and are carrying out tomographic studies of smooth muscle filaments to determine the three-dimensional details of their side-polar structure. In our studies of thin filaments, we are developing new methods of 3D reconstruction to reveal further details of the organization of troponin on actin, and we are combining the reconstructions with crystallographic structures of the thin filament components to produce a 3D thin filament model at the atomic level.

 

Myosin figure
 
Figure 1. 3D reconstruction and atomic fitting of (thick) myosin filament (from Woodhead et al., 2005). Left: 3D reconstruction showing arrangement of myosin heads on filament surface, and subfilaments running parallel to axis in filament backbone. Right: fitting of atomic structure of myosin heads (space-filling colored balls) into reconstruction of one pair of heads. The fitting reveals that the two heads interact with each other, preventing interaction with actin and thereby switching contraction off.
 

Actin figure

Figure 2. 3D reconstruction and atomic fitting of thin filament. Left: 3D reconstruction based on cryo images of thin filaments (from Xu et al., 1999). Actin in gold, tropomyosin in red (myosin blocking position), and green (non-blocking position). Right: fitting of actin atomic structure (yellow, α-carbon chain) into reconstruction of one actin subunit (blue wire). Highlighted in orange are amino acid clusters on actin that are blocked by tropomyosin in blocking position (white arrow). From Vibert et al., 1997.


One or more keywords matched the following items that are connected to Craig, Roger

Item TypeName
Academic Article The troponin tail domain promotes a conformational state of the thin filament that suppresses myosin activity.
Academic Article Helical order in tarantula thick filaments requires the "closed" conformation of the myosin head.
Academic Article Mini-thin filaments regulated by troponin-tropomyosin.
Academic Article Atomic model of a myosin filament in the relaxed state.
Academic Article The tip of the coiled-coil rod determines the filament formation of smooth muscle and nonmuscle myosin.
Academic Article Blebbistatin stabilizes the helical order of myosin filaments by promoting the switch 2 closed state.
Academic Article Head-head interaction characterizes the relaxed state of Limulus muscle myosin filaments.
Academic Article The tail binds to the head-neck domain, inhibiting ATPase activity of myosin VIIA.
Academic Article Mass determination of native smooth muscle myosin filaments by scanning transmission electron microscopy.
Academic Article Ca2+ causes release of myosin heads from the thick filament surface on the milliseconds time scale.
Academic Article Structure and function of myosin filaments.
Academic Article The globular tail domain of myosin Va functions as an inhibitor of the myosin Va motor.
Academic Article The globular tail domain puts on the brake to stop the ATPase cycle of myosin Va.
Academic Article Three-dimensional structure of vertebrate cardiac muscle myosin filaments.
Academic Article Head-head and head-tail interaction: a general mechanism for switching off myosin II activity in cells.
Academic Article Millisecond time-resolved changes occurring in Ca2+-regulated myosin filaments upon relaxation.
Academic Article Understanding the organisation and role of myosin binding protein C in normal striated muscle by comparison with MyBP-C knockout cardiac muscle.
Academic Article Three-dimensional reconstruction of tarantula myosin filaments suggests how phosphorylation may regulate myosin activity.
Academic Article Mechanism of the Ca²+-dependent interaction between S100A4 and tail fragments of nonmuscle myosin heavy chain IIA.
Academic Article Electron microscopy and 3D reconstruction of F-actin decorated with cardiac myosin-binding protein C (cMyBP-C).
Academic Article Direct visualization of myosin-binding protein C bridging myosin and actin filaments in intact muscle.
Academic Article A molecular model of phosphorylation-based activation and potentiation of tarantula muscle thick filaments.
Academic Article Structural basis of the relaxed state of a Ca2+-regulated myosin filament and its evolutionary implications.
Academic Article Cardiac myosin binding protein-C plays no regulatory role in skeletal muscle structure and function.
Concept Myosin Subfragments
Concept Myosin-Light-Chain Kinase
Concept Myosin Heavy Chains
Concept Myosin Light Chains
Concept Myosin Type V
Academic Article Structural changes induced in scallop heavy meromyosin molecules by Ca2+ and ATP.
Academic Article Structure of the myosin filaments of relaxed and rigor vertebrate striated muscle studied by rapid freezing electron microscopy.
Academic Article Electron microscopy of the actin-myosin head complex in the presence of ATP.
Academic Article Direct determination of myosin filament symmetry in scallop striated adductor muscle by rapid freezing and freeze substitution.
Academic Article Myosin filaments isolated from skinned amphibian smooth muscle cells are side-polar.
Academic Article Structural changes induced in Ca2+-regulated myosin filaments by Ca2+ and ATP.
Academic Article Structural changes accompanying phosphorylation of tarantula muscle myosin filaments.
Academic Article Myosin filament structure in vertebrate smooth muscle.
Academic Article Polymerization of myosin on activation of rat anococcygeus smooth muscle.
Academic Article Mechanism of phosphorylation of the regulatory light chain of myosin from tarantula striated muscle.
Academic Article Purification of native myosin filaments from muscle.
Academic Article Different head environments in tarantula thick filaments support a cooperative activation process.
Academic Article Structure, sarcomeric organization, and thin filament binding of cardiac myosin-binding protein-C.
Academic Article Myosin-binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism.
Academic Article Orientation of myosin binding protein C in the cardiac muscle sarcomere determined by domain-specific immuno-EM.
Academic Article An invertebrate smooth muscle with striated muscle myosin filaments.
Academic Article Phosphorylation and calcium antagonistically tune myosin-binding protein C's structure and function.
Academic Article Modulation of striated muscle contraction by binding of myosin binding protein C to actin.
Academic Article Myosin-binding protein C corrects an intrinsic inhomogeneity in cardiac excitation-contraction coupling.
Academic Article Phosphorylation of cardiac myosin binding protein C releases myosin heads from the surface of cardiac thick filaments.
Academic Article Skeletal myosin binding protein-C isoforms regulate thin filament activity in a Ca2+-dependent manner.
Academic Article Interacting-heads motif has been conserved as a mechanism of myosin II inhibition since before the origin of animals.
Academic Article Altered C10 domain in cardiac myosin binding protein-C results in hypertrophic cardiomyopathy.
Academic Article The central role of the tail in switching off 10S myosin II activity.
Academic Article Lattice arrangement of myosin filaments correlates with fiber type in rat skeletal muscle.
Academic Article The mesa trail and the interacting heads motif of myosin II.
Academic Article The myosin interacting-heads motif present in live tarantula muscle explains tetanic and posttetanic phosphorylation mechanisms.
Academic Article Cryo-EM structure of the inhibited (10S) form of myosin II.

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  • Nonmuscle Myosin Type IIB