Alternative S2 Hinge Regions of the Myosin Rod Differentially Affect Muscle Function, Myofibril Dimensions and Myosin Tail Length

Jennifer A. Suggs, Anthony Ross Cammarato, William A. Kronert, Massoud Nikkhoy, Corey M. Dambacher, Aram Megighian, Sanford I. Bernstein

Research output: Contribution to journalArticle

Abstract

Muscle myosin heavy chain (MHC) rod domains intertwine to form alpha-helical coiled-coil dimers; these subsequently multimerize into thick filaments via electrostatic interactions. The subfragment 2/light meromyosin "hinge" region of the MHC rod, located in the C-terminal third of heavy meromyosin, may form a less stable coiled-coil than flanking regions. Partial "melting" of this region has been proposed to result in a helix to random-coil transition. A portion of the Drosophila melanogaster MHC hinge is encoded by mutually exclusive alternative exons 15a and 15b, the use of which correlates with fast (hinge A) or slow (hinge B) muscle physiological properties. To test the functional significance of alternative hinge regions, we constructed transgenic fly lines in which fast muscle isovariant hinge A was switched for slow muscle hinge B in the MHC isoforms of indirect flight and jump muscles. Substitution of the slow muscle hinge B impaired flight ability, increased sarcomere lengths by approximately 13% and resulted in minor disruption to indirect flight muscle sarcomeric structure compared with a transgenic control. With age, residual flight ability decreased rapidly and myofibrils developed peripheral defects. Computational analysis indicates that hinge B has a greater coiled-coil propensity and thus reduced flexibility compared to hinge A. Intriguingly, the MHC rod with hinge B was ∼5 nm longer than myosin with hinge A, consistent with the more rigid coiled-coil conformation predicted for hinge B. Our study demonstrates that hinge B cannot functionally substitute for hinge A in fast muscle types, likely as a result of differences in the molecular structure of the rod, subtle changes in myofibril structure and decreased ability to maintain sarcomere structure in indirect flight muscle myofibrils. Thus, alternative hinges are important in dictating the distinct functional properties of myosin isoforms and the muscles in which they are expressed.

Original languageEnglish (US)
Pages (from-to)1312-1329
Number of pages18
JournalJournal of Molecular Biology
Volume367
Issue number5
DOIs
StatePublished - Apr 13 2007
Externally publishedYes

Fingerprint

Myosin Subfragments
Myofibrils
Myosins
Tail
Muscles
Myosin Heavy Chains
Sarcomeres
Protein Isoforms
Molecular Structure
Drosophila melanogaster
Static Electricity
Diptera
Freezing
Exons

Keywords

  • Drosophila
  • indirect flight muscle
  • myofibril
  • myosin
  • S2 hinge

ASJC Scopus subject areas

  • Virology

Cite this

Alternative S2 Hinge Regions of the Myosin Rod Differentially Affect Muscle Function, Myofibril Dimensions and Myosin Tail Length. / Suggs, Jennifer A.; Cammarato, Anthony Ross; Kronert, William A.; Nikkhoy, Massoud; Dambacher, Corey M.; Megighian, Aram; Bernstein, Sanford I.

In: Journal of Molecular Biology, Vol. 367, No. 5, 13.04.2007, p. 1312-1329.

Research output: Contribution to journalArticle

Suggs, Jennifer A. ; Cammarato, Anthony Ross ; Kronert, William A. ; Nikkhoy, Massoud ; Dambacher, Corey M. ; Megighian, Aram ; Bernstein, Sanford I. / Alternative S2 Hinge Regions of the Myosin Rod Differentially Affect Muscle Function, Myofibril Dimensions and Myosin Tail Length. In: Journal of Molecular Biology. 2007 ; Vol. 367, No. 5. pp. 1312-1329.
@article{0cc8607c960545cda7a0618f23f116ea,
title = "Alternative S2 Hinge Regions of the Myosin Rod Differentially Affect Muscle Function, Myofibril Dimensions and Myosin Tail Length",
abstract = "Muscle myosin heavy chain (MHC) rod domains intertwine to form alpha-helical coiled-coil dimers; these subsequently multimerize into thick filaments via electrostatic interactions. The subfragment 2/light meromyosin {"}hinge{"} region of the MHC rod, located in the C-terminal third of heavy meromyosin, may form a less stable coiled-coil than flanking regions. Partial {"}melting{"} of this region has been proposed to result in a helix to random-coil transition. A portion of the Drosophila melanogaster MHC hinge is encoded by mutually exclusive alternative exons 15a and 15b, the use of which correlates with fast (hinge A) or slow (hinge B) muscle physiological properties. To test the functional significance of alternative hinge regions, we constructed transgenic fly lines in which fast muscle isovariant hinge A was switched for slow muscle hinge B in the MHC isoforms of indirect flight and jump muscles. Substitution of the slow muscle hinge B impaired flight ability, increased sarcomere lengths by approximately 13{\%} and resulted in minor disruption to indirect flight muscle sarcomeric structure compared with a transgenic control. With age, residual flight ability decreased rapidly and myofibrils developed peripheral defects. Computational analysis indicates that hinge B has a greater coiled-coil propensity and thus reduced flexibility compared to hinge A. Intriguingly, the MHC rod with hinge B was ∼5 nm longer than myosin with hinge A, consistent with the more rigid coiled-coil conformation predicted for hinge B. Our study demonstrates that hinge B cannot functionally substitute for hinge A in fast muscle types, likely as a result of differences in the molecular structure of the rod, subtle changes in myofibril structure and decreased ability to maintain sarcomere structure in indirect flight muscle myofibrils. Thus, alternative hinges are important in dictating the distinct functional properties of myosin isoforms and the muscles in which they are expressed.",
keywords = "Drosophila, indirect flight muscle, myofibril, myosin, S2 hinge",
author = "Suggs, {Jennifer A.} and Cammarato, {Anthony Ross} and Kronert, {William A.} and Massoud Nikkhoy and Dambacher, {Corey M.} and Aram Megighian and Bernstein, {Sanford I.}",
year = "2007",
month = "4",
day = "13",
doi = "10.1016/j.jmb.2007.01.045",
language = "English (US)",
volume = "367",
pages = "1312--1329",
journal = "Journal of Molecular Biology",
issn = "0022-2836",
publisher = "Academic Press Inc.",
number = "5",

}

TY - JOUR

T1 - Alternative S2 Hinge Regions of the Myosin Rod Differentially Affect Muscle Function, Myofibril Dimensions and Myosin Tail Length

AU - Suggs, Jennifer A.

AU - Cammarato, Anthony Ross

AU - Kronert, William A.

AU - Nikkhoy, Massoud

AU - Dambacher, Corey M.

AU - Megighian, Aram

AU - Bernstein, Sanford I.

PY - 2007/4/13

Y1 - 2007/4/13

N2 - Muscle myosin heavy chain (MHC) rod domains intertwine to form alpha-helical coiled-coil dimers; these subsequently multimerize into thick filaments via electrostatic interactions. The subfragment 2/light meromyosin "hinge" region of the MHC rod, located in the C-terminal third of heavy meromyosin, may form a less stable coiled-coil than flanking regions. Partial "melting" of this region has been proposed to result in a helix to random-coil transition. A portion of the Drosophila melanogaster MHC hinge is encoded by mutually exclusive alternative exons 15a and 15b, the use of which correlates with fast (hinge A) or slow (hinge B) muscle physiological properties. To test the functional significance of alternative hinge regions, we constructed transgenic fly lines in which fast muscle isovariant hinge A was switched for slow muscle hinge B in the MHC isoforms of indirect flight and jump muscles. Substitution of the slow muscle hinge B impaired flight ability, increased sarcomere lengths by approximately 13% and resulted in minor disruption to indirect flight muscle sarcomeric structure compared with a transgenic control. With age, residual flight ability decreased rapidly and myofibrils developed peripheral defects. Computational analysis indicates that hinge B has a greater coiled-coil propensity and thus reduced flexibility compared to hinge A. Intriguingly, the MHC rod with hinge B was ∼5 nm longer than myosin with hinge A, consistent with the more rigid coiled-coil conformation predicted for hinge B. Our study demonstrates that hinge B cannot functionally substitute for hinge A in fast muscle types, likely as a result of differences in the molecular structure of the rod, subtle changes in myofibril structure and decreased ability to maintain sarcomere structure in indirect flight muscle myofibrils. Thus, alternative hinges are important in dictating the distinct functional properties of myosin isoforms and the muscles in which they are expressed.

AB - Muscle myosin heavy chain (MHC) rod domains intertwine to form alpha-helical coiled-coil dimers; these subsequently multimerize into thick filaments via electrostatic interactions. The subfragment 2/light meromyosin "hinge" region of the MHC rod, located in the C-terminal third of heavy meromyosin, may form a less stable coiled-coil than flanking regions. Partial "melting" of this region has been proposed to result in a helix to random-coil transition. A portion of the Drosophila melanogaster MHC hinge is encoded by mutually exclusive alternative exons 15a and 15b, the use of which correlates with fast (hinge A) or slow (hinge B) muscle physiological properties. To test the functional significance of alternative hinge regions, we constructed transgenic fly lines in which fast muscle isovariant hinge A was switched for slow muscle hinge B in the MHC isoforms of indirect flight and jump muscles. Substitution of the slow muscle hinge B impaired flight ability, increased sarcomere lengths by approximately 13% and resulted in minor disruption to indirect flight muscle sarcomeric structure compared with a transgenic control. With age, residual flight ability decreased rapidly and myofibrils developed peripheral defects. Computational analysis indicates that hinge B has a greater coiled-coil propensity and thus reduced flexibility compared to hinge A. Intriguingly, the MHC rod with hinge B was ∼5 nm longer than myosin with hinge A, consistent with the more rigid coiled-coil conformation predicted for hinge B. Our study demonstrates that hinge B cannot functionally substitute for hinge A in fast muscle types, likely as a result of differences in the molecular structure of the rod, subtle changes in myofibril structure and decreased ability to maintain sarcomere structure in indirect flight muscle myofibrils. Thus, alternative hinges are important in dictating the distinct functional properties of myosin isoforms and the muscles in which they are expressed.

KW - Drosophila

KW - indirect flight muscle

KW - myofibril

KW - myosin

KW - S2 hinge

UR - http://www.scopus.com/inward/record.url?scp=33947150032&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33947150032&partnerID=8YFLogxK

U2 - 10.1016/j.jmb.2007.01.045

DO - 10.1016/j.jmb.2007.01.045

M3 - Article

C2 - 17316684

AN - SCOPUS:33947150032

VL - 367

SP - 1312

EP - 1329

JO - Journal of Molecular Biology

JF - Journal of Molecular Biology

SN - 0022-2836

IS - 5

ER -