Abstract Details

Title CPNA-1, a Copine Domain Protein, Is Located at Integrin Adhesion Sites, and Is Required for Myofilament Stability in C. elegans

Topic Muscle Disease/Neuromuscular Junction

Presentation(s) P07 - (-)

Poster/Presentation
Number 037

Objective

Background BACKGROUND: Mutations in multiple genes are responsible for various human muscular dystrophies, and many of these encode proteins located near the plasma or nuclear membranes. C. elegans is an excellent genetic model system for discovering new components of muscle. Because sarcomere structure / components are conserved, discoveries made in C. elegans have relevance for human muscle disease.

Design/Methods DESIGN/METHODS: Large scale RNAi screening and yeast 2-hybrid library screening were independently used to identify a new sarcomeric component, CPNA-1. An intragenic deletion was used to determine the null state for cpna-1. Antibodies and a GFP fusion were used to determine the localization of CPNA-1. Proteins that interact with CPNA-1 were identified by yeast 2-hybrid screening and confirmed by biochemical approaches.

Results RESULTS: CPNA-1 contains a copine domain, a domain of largely unknown function. The closest human homolog is an alternatively spliced isoform of COPINE V. CPNA-1 is localized to integrin attachment sites (M-line and Z-disk analogs) in C. elegans striated muscle. CPNA-1 binds to other sarcomeric proteins including PAT-6 (parvin in humans) and UNC-89 (obscurin in humans). Proper CPNA-1 localization depends on PAT-6 in embryonic and adult muscle. Nematodes lacking cpna-1 arrest at the 2-fold stage of embryogenesis and display disorganization of the myofilament lattice. A thick filament myosin heavy chain and the M-line component UNC-89 are initially able to localize properly in cpna-1 null mutant embryos. However, when contraction would begin, this myosin and UNC-89 become mislocalized and the animals die.

Conclusions CONCLUSIONS: A novel essential muscle gene cpna-1 has been identified and it is proposed that CPNA-1 acts as a linker between integrin associated protein PAT-6 and downstream components to play a role in myofilament stability.

Authors/Disclosures
Ge Xiong, MD (University of California At San Francisco) PRESENTER	The institution of Dr. Xiong has received research support from Argenx.
	No disclosure on file
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