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Padrón lab publications
Effects of myosin variants on interacting-heads motif (IHM) explain distinct hypertrophic (HCM) and dilated (DCM) cardiomyopathy phenotypes
Lorenzo Alamo, James S. Ware, Antonio Pinto, Richard E. Gillilan, Jonathan G. Seidman, Chrisitine E. Seidman & Raúl Padrón
eLife 2017;6:e24634
doi: 10.7554/eLife.24634
Padron lab
Alamo et al. 2017 Fig. 1
Cardiac β-myosin variants cause hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM) by disrupting sarcomere contraction and relaxation.

The locations of variants on isolated myosin head structures predict contractility effects but not the prominent relaxation and energetic deficits that characterize HCM. During relaxation, pairs of myosins form interacting-heads motif (IHM) structures that with other sarcomere proteins establish an energy-saving, super-relaxed (SRX) state.

Using a human β-cardiac myosin IHM quasi-atomic model (PDB 5TBY), we defined interactions sites between adjacent myosin heads and associated protein partners, and then analyzed rare variants from 6112 HCM and 1315 DCM patients and 33,370 ExAC controls. HCM variants, 72% that changed electrostatic charges, disproportionately altered IHM interaction residues (expected 23%; HCM 54%, p=2.6×10−19; DCM 26%, p=0.66; controls 20%, p=0.23).
HCM variant locations predict impaired IHM formation and stability, and attenuation of the SRX state - accounting for altered contractility, reduced diastolic relaxation, and increased energy consumption, that fully characterizes HCM pathogenesis.
Press releases

IVIC (English)  Noticias

       Howard Hughes Medical Institute (HHMI) News
Lessons from a Tarantula: Spider muscles reveals details about mutations that disrupt heart relaxation by Hanae Armitage)

       Harvard Medical School News 
Lessons from a Tarantula: Spider muscles reveals details about mutations that disrupt heart relaxation   by Hanae Armitage

Imperial College London News 
Spider proteins offer new insight into human heart conditions  by Ryan O´Hare

Que hacen los academicos (ACAL)

Human beta-cardiac myosin interacting heads motif (IHM) PDB 5TBY
  ...


From right to left:  José Reverol, Sebastian Duno, Galax Joya, Ruth García, Gustavo Márquez, Antonio Pinto, Lorenzo Alamo and Raúl Padrón. 13-3-2017 Blue tarantula
 October 2015
...
The research of the Padrón Lab was supported by the Howard Hughes Medical Institute (HHMI) from 1997 to 2011
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Padrón Lab People - Academic tree
Current members - February 2017

Students
Br. Sebastián Duno
Undergraduate student
Br. José Reverol
Graduate student

Research Associates
M. Sc. Galax Joya
Research Associate
M. Sc. Ruth García
Research Associate
Dr. Gustavo Marquez
Research Associate

Retired Research Associates working ad honorem
Electronic Eng. Antonio Pinto EE
Research Associate
Lic. Biology Lorenzo  Alamo
Research Associate

Former members

Research Investigators
Dr. Guidenn Sulbarán
Associated Investigator
(France 20-2-2016)

Former Research Associates

Dr. Jose Reinaldo Guerrero
Retired
M. Sc. Maristela Granados

Eng. Franklin  Méndez
Research Associate
(Colombia 26-8-2016)
Eng. Antonio Pinto EE
Retired
Dr. Aivett Bilbao
(Now in U.S.A.)
Lic. Lorenzo  Alamo
Retired

Postdoctoral Fellows
Dr. Carlos Hidalgo
1997-2000 (Now in U.S.A.)
Dr. Rosalba Rodriguez
2009-2012 (Now at IVIC-CBE)
Dr. Guidenn Sulbáran
2009-2012 (France 20-2-2016)

Dr. Lucía Proietti d´Speratti
(Now in U.S.A. 1-2-2016)

Ph.D.

Dr. Jose Reinaldo Guerrero
1995
Dr. Julio Ortiz
2002 (Now in Germany)
Dr. María Elena Zoghbi
2003 (Now in U.S.A.)
Dr. Reicy Brito
2010 (Now in Spain)

M.Sc.

Dr. Nelly Panté
1986
(Now in Canada)
Dr. José Reinaldo Guerrero
1989
M. Sc. Maristela Granados
1993
M. Sc. Karina Temperini
2001
(Now in Argentina)

M. Sc. Nelitza  Linarez
2001
Lic. Antonio Biasutto
2011-
(Now in U.K.)

Bachelors

Dr.Hernando Sosa
1986
(Now in U.S.A.)
Lic. Patricia Valero
1991
Lic. Jackeline Rodriguez
1991
M. Sc. Claire L. Riggs
2010
(Now in U.S.A.)

Visitors

Dr.Robert Perz-Edwards
1991-1992
(Now in U.S.A.)

Leroy Lindsay MD
2005
(Now in Spain)

Mina-Han Tran
2008/2009
(Now in U.S.A.)

..
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.
Raúl Padrón
Structure and function of the
thick filaments of striated muscle

... ...
Tarantula thick filament 3D-reconstruction
Atomic model of
tarantula thick filament
2007 Venezuelan
postal stamp
Transverse section of the frozen-hydrated tarantula 3D-map

Dr. Raúl Padrón is Emeritus Investigator,  Center of Structural Biology, Venezuelan Institute for Scientific Research (IVIC), Caracas.  After his postdoctoral work at the MRC Laboratory of Molecular Biology (Cambridge, UK), he founded in 1997 the Department of Structural Biology of IVIC, where he was an International Research Scholar of the Howard Hughes Medical Institute (HHMI) until 2011. He has devoted his career to study the structure and function of thick filaments from striated muscle.  In 2005, his group (in collaboration with Dr. Roger Craig and Dr. Ed Egelman) elucidated the atomic structure of the thick filaments from striated muscle; and in 2011 proposed a molecular mechanism explaining the activation of thick filaments on muscle contraction. His honors include: Polar Prize (1991); CONICIT Biology Prizes (1989, 1990, 1996); FONACIT Biology Prize (2005); Rafael Rangel Prize (2008); and the National Prize in Science and Technology of Venezuela (2008). He is a member of the Latin-American Academy of Sciences and The World Academy of Sciences (TWAS).

Padrón lab questions: How thick filaments are relaxed or activated?

Myosin-2 molecules are molecular motors that drive muscle contraction and cell motility. This important family of conventional myosins has two heavy chains and two pairs of light chains. The two heavy chains fold into α-helices that twist around each other forming a long, coil-coiled tail with two globular heads at one end. Each head has a motor and a regulatory domain. The regulatory domain – involved in the Ca2+ control of contraction – includes a pair of essential (ELC) and regulatory (RLC) light chains. The tails of several hundred myosin molecules pack together in an antiparallel way, forming a thick filament with the heads helically arranged on the surface. The basic contractile unit of striated muscle is the sarcomere, formed by the overlapping of myosin filaments with actin-containing thin filaments. Activation in many muscles requires phosphorylation of the RLC, causing release of the heads from the filament backbone, followed by cyclic interaction with the thin filaments, producing ATP-powered force and sarcomere shortening (1). Determining the molecular structure of the thick (myosin) filaments is essential for understanding muscle function, in both healthy and diseased states (2).

Padrón lab achievements
How tarantula thick filament cuasi-atomic structure was solved?

The myosin interacting-heads motif
Our early work3,4 opened the way to understand the structure and function of the thick filaments using a model system (tarantula muscle). We recently made a crucial advance in this work using state-of-the-art techniques (cryo-electron microscopy (EM), single particle reconstruction and atomic fitting).
This led to a critical breakthrough – obtaining the first atomic model of a relaxed thick filament in the native (unfixed, unstained, hydrated) state5. The 3D-map revealed that in the relaxed state the two heads of each myosin molecule interact with each other.
Surprisingly, this arrangement was similar to the structure observed in 2D crystals of myosin molecules purified from the smooth muscle of a vertebrate (chicken gizzard)6. We also discovered a new intramolecular interaction between a positively charged loop of the free head and a negatively charged region of its own tail7 (subfragment 2 (S2)).
Myosin RLC
EU090070.1
PDB
3DTP
EMD
1950
Cuasi-atomic model
of thick filament
Our studies thus showed that this unusual, asymmetric head organization was not an artifact of myosin isolation or crystallization, but occurred in vivo.
The conservation and uniqueness of this motif across the vast evolutionary distance between vertebrate smooth muscle and invertebrate striated muscle suggested that it was of fundamental functional importance for preserving the relaxed (“off”) state in most or all muscles.
How myosin thick filaments are relaxed?

Analysis of the interaction between the two heads shows that one head (“free”) physically blocks the actin-binding site of the other head (“blocked”); this interaction simultaneously blocks the ATPase site of the free head. This head-head interaction immediately suggests a simple mechanism to explain relaxation – by switching off the two heads in different ways.  In further analysis we discovered a new intermolecular interaction between adjacent motifs7 that would further stabilize the off-state.
The myosin interacting-heads motif is widelly spread
Subsequent studies have demonstrated the presence of this motif in non-muscle cells, and in smooth and striated muscles of other species, confirming its widespread occurrence and the importance of tarantula thick filaments as a model system for studying thick filament structure and function.
The myosin interacting/heads motif is present in:
Nonmuscle
Smooth muscle
Striated muscle
Skeletal muscle
Cardiac muscle
Tarantula, Limulus, scorpion, scallop, Schistosoma mansoni
mouse, human, zebrafish
Thick filaments from Schistosoma mansoni smooth muscle
All animals have the ability to move. In most animals, striated musclesmove the body and smooth muscles the internal organs. In both muscles, contraction results from interaction between myosin and actin filaments. Based on vertebrate studies, smooth and striated muscles are thought to have different protein components and filament structures. We have studied muscle ultrastructure in the parasite Schistosoma mansoni, where we find that this view is not supported. This invertebrate possesses only smooth muscles, yet its myosin sequence and filament structure are identical to those of striated muscle, while its actin filaments are smooth muscle-like. Such “hybrid” muscles may be common in other invertebrates. This finding challenges the paradigm that smooth and striated muscles always have different components.


     Muscle tissues are classically divided into two major types, depending on the presence or absence of striations. In striated muscles, the actin filaments are anchored at Z-lines and the myosin and actin filaments are in register, whereas in smooth muscles, the actin filaments are attached to dense bodies and the myosin and actin filaments are out of register. The structure of the filaments in smooth muscles is also different from that in striated muscles. Here we have studied the structure of myosin filaments from the smooth muscles of the human parasite Schistosoma mansoni. We find, surprisingly, that they are indistinguishable from those in an arthropod striated muscle (EMD-6370 and 3JAX ). This structural similarity is supported by sequence comparison between the schistosome myosin II heavy chain and known striated muscle myosins. In contrast, the actin filaments of schistosomes are similar to those of smooth muscles, lacking troponin-dependent regulation. We conclude that schistosome muscles are hybrids, containing striated muscle-like myosin filaments and smooth muscle-like actin filaments in a smooth muscle architecture. This surprising finding has broad significance for understanding how muscles are built and how they evolved, and challenges the paradigm that smooth and striated muscles always have distinctly different components.

Intra- and inter-molecular interactions

We also discovered a new intramolecular interaction between a positively charged loop of the free head and a negatively charged region of its own tail7 (subfragment 2 (S2)). This interaction could help electrostatically dock the head onto its tail. This loop was originally designated the “cardiomyopathy loop” (CM) because the first mutations reported to cause inherited hypertrophic cardiomyopathy (HCM) were in its positively charged R403 amino acid.
How muscle thick filaments are activated?
A Molecular Model of Phosphorylation-Based Activation and Potentiation of Tarantula Muscle Thick Filaments
Our analysis of the head organization, together with motility assays, sequence analysis and mass spectrometry observations suggests a molecular model for muscle activation in which heads are phosphorylated sequentially by protein kinase C (PKC) and myosin light chain kinase (MLCK) in a way that can explain both force development and post-tetanic potentiation in striated muscle8.
The Cooperative Phosphorylation Mechanism for Thick Filament Activation
The cooperative phosphorylation mechanism for activation of tarantula thick filaments (8,16): in the relaxed state (a) free heads have their Ser-35 constitutively monophosphorylated (pSer-35), enabling them to sway away in and out (swaying heads, double arrows). The blocked heads cannot be released as their Ser-45 are nonphosphorylated. On activation (b–d), when Ca2+ concentration is high for long enough to activate MLCK, a swaying head is permanently released (arrow) by biphosphorylation of its N-terminal extension (b). This outward movement of the free head leaves an open space (b), allowing access of activated MLCK to phosphorylate the Ser-45 N-terminal extension of the above blocked head (pSer-45), allowing this head to sway (c). This phosphorylation hinders the docking back of its partner swaying free head, which thus also becomes mobile even without biphosphorylation (d, top free head) opening a new space above (d). Thus, biphosphorylation of a swaying free head induces the cooperative unzipping of the neighbor blocked and free heads, releasing them from the backbone; and so on along the helix (7,8).
Sequential myosin phosphorylation activates thick filament via a disorder-order transition
The cooperative phosphorylation-controlled mechanism for recruiting active heads in tarantula thick filament activation (a–d) (8,16) showing the two actuators (red and yellow boxes) that control the sequential release of free (red box) and blocked (yellow box) myosin heads on tarantula thick filament activation. On the left three myosin interacting-head motifs are shown along one thick filament helix with unphosphorylated RLC NTEs (bare zone at the top). In the ‘‘activating actuator’’ (red boxes) the Ser45 phosphorylation of the constitutively Ser35 monophosphorylated swaying free heads in (a) induces a complete disorder-to-order transition. This transition fully elongates the helix P along the helix A (depicted as a blue cylinder) by establishing three salt bridges pSer35/Arg38,Arg39, and Arg42 (b). This elongation suggests that the diphosphorylated NTE would possibly stiffen, altering the free head regulatory domain, producing the release of the swaying free heads (i.e. released heads) in (b). In the ‘‘potentiating actuator’’ (yellow boxes), the Ser45 monophosphorylation of the unphosphorylated blocked head in (b), does not produce any conformational change on the NTE, but only a decrease of its charge by 2. This could weaken the interaction of its NTE with a loop on the motor domain of the neighbour free head, allowing it to sway away (c, curved arrows), producing the release of its partner constitutively Ser35 monophosphorylated free head (d, arrow).
Myosin free head RLC phosphorylation stiffens N-terminal extension,
releasing it and blocking its docking back

The cooperative phosphorylation-controlled mechanism for recruiting active heads in tarantula thick filament activation (a-d). (8,16,17) The three myosin interacting-head motifs on the left are shown along one thick filament helix with their entire RLC NTEs unphosphorylated (bare zone at the top). This mechanism shows how the Ser45 phosphorylation of the constitutive Ser35 monophosphorylated swaying free head NTE (b, centre interacting-heads motif) hinders its docking back making it permanently mobile (b, arrow). Two actuators (red and yellow boxes) control the sequential release of myosin heads on tarantula thick filament activation. Activating actuator (red boxes): according to our MD simulations the activating actuator is based on a disorder-to-order transition of the RLC NTE, which induces its elongation in accordance with the increase of the static and dynamic persistence lengths PLs and PLd. This implies a substantial straightening and rigidification of the diphosphorylated NTE, modifying the free head regulatory domain, and producing the release of these heads (b). The 416-fold increase in the free head NTE straightness and rigidity upon diphosphorylation would hinder docking back of this head after swaying away as it could not recover its original interacting stereospecific disposition, hindering as well the S2 intramolecular interaction, thus becoming relaxed and mobile (b, arrow). The constitutively Ser35 monophosphorylated free head diphosphorylation induces a disorder-to-order transition which fully elongates the helix P along the helix A by establishing three salt bridges pSer35/Arg38,Arg39, and pSer45/Arg42. Potentiating actuator (yellow boxes): in contrast to the activating actuator on the free head, the potentiation actuator on the blocked head is not based on a disorderto-order transition of the RLC NTE. The blocked head Ser45 monophosphorylation does not produce any conformational change on the NTE, except a salt bridge between pSer45 and Lys39 or pSer45 and Lys37.17 A net negative charge reduction of 2 and an 1.8-fold increase in dynamic persistence length (PLd), suggesting that blocked head NTE monophosphorylation at Ser45 makes it more rigid, hindering the docking back of its partner free head, making it also relaxed and mobile (d, top arrow). This in turn could weaken the blocked head RLC NTE electrostatic interaction with a loop on the motor domain of the neighbour free head, making the blocked head to sway away (c). This is functionally important since the blocked head monophosphorylation at Ser45 by MLCK is an effective way to recruit potentiating heads (c). FH and BH: free and blocked heads.
Conserved intramolecular interactions maintain myosin interacting-heads motifs
explaining tarantula muscle super-relaxed state structural basis

Tarantula striated muscle is an outstanding system for understanding the molecular organization of myosin filaments. 3D reconstruction based on cryo-EM images and single-particle image processing revealed that in a relaxed state, myosin molecules undergo intramolecular head–head interactions, explaining why head activity switches off. The filament model obtained by rigidly docking a chicken smooth muscle myosin structure to the reconstruction was improved by flexibly fitting an atomic model built by mixing structures from different species to a tilt-corrected 2-nm 3D map of frozen-hydrated tarantula thick filament. We used heavy and light chain sequences from tarantula myosin to build a single-species homology model of two heavy meromyosin interacting-heads motifs (IHMs). The flexibly fitted model includes previously missing loops and shows five intramolecular and five intermolecular interactions that keep the IHM in a compact off structure, forming four helical tracks of IHMs around the backbone. The residues involved in these interactions are oppositely charged, and their sequence conservation suggests that IHM is present across animal species. The new model, PDB 3JBH, explains the structural origin of the ATP turnover rates detected in relaxed tarantula muscle by ascribing the very slow rate to docked unphosphorylated heads, the slow rate to phosphorylated docked heads, and the fast rate to phosphorylated undocked heads. The conservation of intramolecular interactions across animal species and presence of IHM in bilaterians suggest that a super-relaxed state should be maintained, as it plays a role in saving ATP in skeletal, cardiac, and smooth muscle.
 Tarantula Myosin Interacting-Heads Motif (IHM) PDB 3JBH
PDB 3JBH
An atomic model of two heavy meromyosin interacting-heads motifs (IHM) is achieved
Conserved intramolecular interactions suggests IHM presence across animal species
These interactions and IHM model explains the structural origin of super-relaxation
The super-relaxed state should also be conserved across animal species
...
Cooperative Phosphorylation Activation (CPA) model explain tarantula super-relaxed state structural basis
Hypertrophic cardiomyopathy mutations
Interestingly a cluster of nine HCM-causing mutations in the S2 tail and the CM loop reverse (S2) or diminish (CM loop) the charge of their amino acid residues7. The electrostatic interactions immediately suggest a simple mechanism to explain how the tail and loop mutations – in principle physically unrelated – could lead to disease, being concentrated in a functionally important interaction. Reversal of the charges on one side of the interaction, due to mutation, will diminish the CM loop-S2 attractive force, nullifying its docking function and forcing the muscle to compensate in some way.
Recently, 37 mutations associated with hypertrophic and dilated (DCM) cardiomyopathy were mapped to the tarantula motif by the German Competence Network Heart Failure9. They interpreted their mapping as suggesting “random distribution [over the different myosin domains] rather than disease-specific clustering of mutations causing HCM and DCM”9. However, the authors did not take into account the detailed 3D organization and interactions of the heads and tail in the tarantula motif7. The presence of the motif in cardiac muscle of mouse10 and its recent confirmation in human11 are of particular interest, as this implies that the intra- and intermolecular interactions seen in tarantula5,7 are also conserved in cardiac muscle. It is therefore very important to reassess this mapping by looking for clusters of mutations in relation to these interactions instead of only the protein domains. Understanding further details of these interactions, as we are currently working on in collaboration with Dr. Christine Seidman, Dr. Jonathan Seidman and Dr.James Ware, may provide new insights into the mechanism of HCM.
Manuscript in preparation
Visualization of MyBP-C in cardiac thick filaments
There are important differences between the thick filaments of invertebrate and vertebrate striated muscles. Invertebrate filaments contain a core of paramyosin (similar to the myosin tail), making them more rigid. In contrast, vertebrate thick filaments lack paramyosin, but contain accessory proteins, including myosin binding protein C (MyBP-C), present at regular intervals in the middle one-third of each half filament12. Phosphorylation of the cardiac isoform, cMyBP-C, has a key role in modulating cardiac function13. In addition to binding to myosin and titin via its C-terminus, cMyBP-C can also interact in vitro (via its N-terminus) with F-actin14. However, the in vivo significance of this binding has been uncertain.
We visualized for the first time the bridging of thick and thin filaments by MyBP-C15 in electron tomograms of thick filaments in the intact sarcomere. This supports the relevance of the in vtro data and suggests a structural basis for MyBP-C’s modulation of cardiac contraction. Understanding MyBP-C function is critically important as mutations of cMyBP-C are a major cause of HCM affecting 60 million people worldwide13.

Quasi-atomic model of the tarantula thick filament
Manuscript in preparation
Padrón lab publications
Publications of the Padrón Lab PubMed list Google Scholars
Quoted references
1. Huxley, H. E. (1969). The mechanism of muscular contraction. Science 164, 1356-1365.
2. Craig, R. & Padrón, R. (2004). Molecular structure of the sarcomere. In Myology (Engel, A. G. & Franzini-Armstrong, C., eds), pp. 129-166, 3rd ed., McGraw-Hill, Inc., New York.

3. Crowther, R. A., Padrón, R. & Craig, R. (1985). Arrangement of the heads of myosin in relaxed thick filaments from tarantula muscle. J. Mol. Biol. 184, 429-439.
4. Craig, R., Padrón, R. & Kendrick-Jones, J. (1987). Structural changes accompanying phosphorylation of tarantula muscle myosin filaments. J. Cell Biol. 105, 1319-1327.
5. Woodhead, J. L., Zhao, F. Q., Craig, R., Egelman, E. H., Alamo, L. & Padrón, R. (2005). Atomic model of a myosin filament in the relaxed state. Nature 436, 1195-1199.
6. Wendt, T., Taylor, D., Trybus, K. M. & Taylor, K. (2001). Three-dimensional image reconstruction of dephosphorylated smooth muscle heavy meromyosin reveals asymmetry in the interaction between myosin heads and placement of subfragment 2. Proc. Natl. Acad. Sci. U. S. A. 98, 4361-4366.
7. Alamo, L., Wriggers, W., Pinto, A., Bartoli, F., Salazar, L., Zhao, F. Q., Craig, R. & Padrón, R. (2008). Three-dimensional reconstruction of tarantula myosin filaments suggests how phosphorylation may regulate myosin activity. J. Mol. Biol. 384, 780-797.
8. Brito, R., Alamo, L., Lundberg, U., Guerrero, J. R., Pinto, A., Sulbaran, G., Gawinowicz, M. A., Craig, R. & Padrón, R. (2011). A molecular model of phosphorylation-based activation and potentiation of tarantula muscle thick filaments. J. Mol. Biol. 414, 44-61.
9. Waldmuller, S., Erdmann, J., Binner, P., Gelbrich, G., Pankuweit, S., Geier, C., Timmermann, B., Haremza, J., Perrot, A., Scheer, S., Wachter, R., Schulze-Waltrup, N., Dermintzoglou, A., Schonberger, J., Zeh, W., Jurmann, B., Brodherr, T., Borgel, J., Farr, M., Milting, H., Blankenfeldt, W., Reinhardt, R., Ozcelik, C., Osterziel, K. J., Loeffler, M., Maisch, B., Regitz-Zagrosek, V., Schunkert, H. & Scheffold, T. (2011). Novel correlations between the genotype and the phenotype of hypertrophic and dilated cardiomyopathy: results from the German Competence Network Heart Failure. Eur. J. Heart Fail. 13, 1185-1192.
10. Zoghbi, M. E., Woodhead, J. L., Moss, R. L. & Craig, R. (2008). Three-dimensional structure of vertebrate cardiac muscle myosin filaments. Proc. Natl. Acad. Sci. U. S. A. 105, 2386-2390.
11. AL-Khayat, H. A., Kensler, R. W., Squire, J. M., Marston, S. B., and Morris, E. P. (2012) 3-Dimensional structure of human cardiac muscle myosin filaments by electron microscopy and single particle analysis. Biophys. J. 102(3) 149a-150a
12. Ackermann, M. A. & Kontrogianni-Konstantopoulos, A. (2011). Myosin binding protein-C: a regulator of actomyosin interaction in striated muscle. J. Biomed. Biotechnol. 2011, 636403. 13.   Barefield, D. & Sadayappan, S. (2010). Phosphorylation and function of cardiac myosin binding protein-C in health and disease. J. Mol. Cell Cardiol. 48, 866-875.
14. Shaffer, J. F., Kensler, R. W. & Harris, S. P. (2009). The myosin-binding protein C motif binds to F-actin in a phosphorylation-sensitive manner. J. Biol. Chem. 284, 12318-12327.
15. Luther, P. K., Winkler, H., Taylor, K., Zoghbi, M. E., Craig, R., Padrón, R., Squire, J. M. & Liu, J. (2011). Direct visualization of myosin-binding protein C  bridging myosin and actin filaments in intact muscle. Proc. Natl. Acad. Sci. U. S. A 108, 11423-11428.
16.-
G. Sulbarán, A. Biasutto, L. Alamo, C. Riggs, A. Pinto, F. Mendez, R. Craig and R. Padrón. (2013). Different head environments in tarantula thick filaments support a cooperative activation process. Biophys. J. 105: 2114-2122, 2013.
17.- Espinoza-Fonseca, M., Alamo, L., Pinto, A., Thomas, D. Padrón, R. (2015) Sequential Myosin Phosphorylation Activates Tarantula Thick Filament via Disorder-Order Transition. Mol. BioSystem. Accepted.  DOI: 10.1039/c5mb00162e.
18.- Alamo, L., Li, X., Espinoza-Fonseca, L.,  Pinto, A., Thomas, D., Lehman, W. and Padrón, R. (2015) Tarantula Myosin Free head Regulatory Light Chain Phosphorylation Stiffens N-terminal Extension releasing it and blocking its docking back. Mol. BioSystem. Accepted. DOI: 10.1039/c5mb00163c.



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