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Title: Skip residues modulate the structural properties of the myosin rod and guide thick filament assembly

The rod of sarcomeric myosins directs thick filament assembly and is characterized by the insertion of four skip residues that introduce discontinuities in the coiled-coil heptad repeats. We report in this paper that the regions surrounding the first three skip residues share high structural similarity despite their low sequence homology. Near each of these skip residues, the coiled-coil transitions to a nonclose-packed structure inducing local relaxation of the superhelical pitch. Moreover, molecular dynamics suggest that these distorted regions can assume different conformationally stable states. In contrast, the last skip residue region constitutes a true molecular hinge, providing C-terminal rod flexibility. Assembly of myosin with mutated skip residues in cardiomyocytes shows that the functional importance of each skip residue is associated with rod position and reveals the unique role of the molecular hinge in promoting myosin antiparallel packing. By defining the biophysical properties of the rod, the structures and molecular dynamic calculations presented here provide insight into thick filament formation, and highlight the structural differences occurring between the coiled-coils of myosin and the stereotypical tropomyosin. Finally, in addition to extending our knowledge into the conformational and biological properties of coiled-coil discontinuities, the molecular characterization of the four myosin skip residues alsomore » provides a guide to modeling the effects of rod mutations causing cardiac and skeletal myopathies.« less
Authors:
 [1] ;  [2] ;  [3] ;  [2] ;  [3] ;  [1] ;  [3] ;  [2] ;  [1]
  1. Univ. of Wisconsin, Madison, WI (United States). Dept. of Biochemistry
  2. Univ. of Colorado, Boulder, CO (United States). Dept. of Molecular, Cellular, and Developmental Biology. Bio Frontiers Inst.
  3. Univ. of Wisconsin, Madison, WI (United States). Dept. of Chemistry. Theoretical Chemistry Inst.
Publication Date:
OSTI Identifier:
1213724
Grant/Contract Number:
W-31-109-ENG-38; R21 HL111237; R01 GM29090; NSF-CHE1300209
Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 112; Journal Issue: 29; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Research Org:
Univ. of Wisconsin, Madison, WI (United States); Univ. of Colorado, Boulder, CO (United States)
Sponsoring Org:
USDOE Office of Science (SC); National Inst. of Health (NIH) (United States); National Science Foundation (NSF)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; myosin; cardiac/skeletal myopathies; molecular dynamics; coiled-coils; protein structure