Imperial College London

ProfessorSteveMarston

Faculty of MedicineNational Heart & Lung Institute

(Non-Clinical) Professor in Cardiovascular Biochemistry
 
 
 
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Contact

 

+44 (0)20 7594 2732s.marston Website

 
 
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Location

 

433ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Rynkiewicz:2017:10.1016/j.bpj.2017.10.004,
author = {Rynkiewicz, MJ and Prum, T and Hollenberg, S and Kiani, FA and Fagnant, PM and Marston, SB and Trybus, KM and Fischer, S and Moore, JR and Lehman, W},
doi = {10.1016/j.bpj.2017.10.004},
journal = {Biophysical Journal},
pages = {2444--2451},
title = {Tropomyosin Must Interact Weakly with Actin to Effectively Regulate Thin Filament Function.},
url = {http://dx.doi.org/10.1016/j.bpj.2017.10.004},
volume = {113},
year = {2017}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - Elongated tropomyosin, associated with actin-subunits along the surface of thin filaments, makes electrostatic interactions with clusters of conserved residues, K326, K328, and R147, on actin. The association is weak, permitting low-energy cost regulatory movement of tropomyosin across the filament during muscle activation. Interestingly, acidic D292 on actin, also evolutionarily conserved, lies adjacent to the three-residue cluster of basic amino acids and thus may moderate the combined local positive charge, diminishing tropomyosin-actin interaction and facilitating regulatory-switching. Indeed, charge neutralization of D292 is connected to muscle hypotonia in individuals with D292V actin mutations and linked to congenital fiber-type disproportion. Here, the D292V mutation may predispose tropomyosin-actin positioning to a myosin-blocking state, aberrantly favoring muscle relaxation, thus mimicking the low-Ca2+ effect of troponin even in activated muscles. To test this hypothesis, interaction energetics and in vitro function of wild-type and D292V filaments were measured. Energy landscapes based on F-actin-tropomyosin models show the mutation localizes tropomyosin in a blocked-state position on actin defined by a deeper energy minimum, consistent with augmented steric-interference of actin-myosin binding. In addition, whereas myosin-dependent motility of troponin/tropomyosin-free D292V F-actin is normal, motility is dramatically inhibited after addition of tropomyosin to the mutant actin. Thus, D292V-induced blocked-state stabilization appears to disrupt the delicately poised energy balance governing thin filament regulation. Our results validate the premise that stereospecific but necessarily weak binding of tropomyosin to F-actin is required for effective thin filament function.
AU - Rynkiewicz,MJ
AU - Prum,T
AU - Hollenberg,S
AU - Kiani,FA
AU - Fagnant,PM
AU - Marston,SB
AU - Trybus,KM
AU - Fischer,S
AU - Moore,JR
AU - Lehman,W
DO - 10.1016/j.bpj.2017.10.004
EP - 2451
PY - 2017///
SN - 0006-3495
SP - 2444
TI - Tropomyosin Must Interact Weakly with Actin to Effectively Regulate Thin Filament Function.
T2 - Biophysical Journal
UR - http://dx.doi.org/10.1016/j.bpj.2017.10.004
UR - http://hdl.handle.net/10044/1/55291
VL - 113
ER -