HOMEPRODUCTSSERVICESCOMPANYCONTACTFAQResearchDictionaryPharmaMobileSign Up FREE or Login

Mutations in Drosophila myosin rod cause defects in myofibril assembly.

Abstract
The roles of myosin during muscle contraction are well studied, but how different domains of this protein are involved in myofibril assembly in vivo is far less understood. The indirect flight muscles (IFMs) of Drosophila melanogaster provide a good model for understanding muscle development and function in vivo. We show that two missense mutations in the rod region of the myosin heavy-chain gene, Mhc, give rise to IFM defects and abnormal myofibrils. These defects likely result from thick filament abnormalities that manifest during early sarcomere development or later by hypercontraction. The thick filament defects are accompanied by marked reduction in accumulation of flightin, a myosin binding protein, and its phosphorylated forms, which are required to stabilise thick filaments. We investigated with purified rod fragments whether the mutations affect the coiled-coil structure, rod aggregate size or rod stability. No significant changes in these parameters were detected, except for rod thermodynamic stability in one mutation. Molecular dynamics simulations suggest that these mutations may produce localised rod instabilities. We conclude that the aberrant myofibrils are a result of thick filament defects, but that these in vivo effects cannot be detected in vitro using the biophysical techniques employed. The in vivo investigation of these mutant phenotypes in IFM development and function provides a useful platform for studying myosin rod and thick filament formation generically, with application to the aetiology of human myosin rod myopathies.
AuthorsSheetal S Salvi, R Pravin Kumar, Nallur B Ramachandra, John C Sparrow, Upendra Nongthomba
JournalJournal of molecular biology (J Mol Biol) Vol. 419 Issue 1-2 Pg. 22-40 (May 25 2012) ISSN: 1089-8638 [Electronic] England
PMID22370558 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Ltd. All rights reserved.
Chemical References
  • Drosophila Proteins
  • Filamins
  • Muscle Proteins
  • Myosin Subfragments
  • fln protein, Drosophila
  • Myosin Heavy Chains
Topics
  • Amino Acid Sequence
  • Animals
  • Drosophila Proteins (chemistry, genetics, metabolism)
  • Drosophila melanogaster
  • Filamins
  • Flight, Animal (physiology)
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Muscle Contraction
  • Muscle Proteins (chemistry, genetics, metabolism)
  • Mutation, Missense
  • Myofibrils (chemistry, genetics, metabolism, ultrastructure)
  • Myosin Heavy Chains (chemistry, genetics, metabolism)
  • Myosin Subfragments (chemistry, genetics, metabolism)
  • Phenotype
  • Phosphorylation (genetics)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!


Choose Username:
Email:
Password:
Verify Password: