ArticleProtein science : a publication of the Protein Society2015
Biophysical characterization of naturally occurring titin M10 mutations.
Article in Protein science : a publication of the Protein Society, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 26 citations in OpenAlex.
- A comprehensive framework for the interpretation of TTN missense variants.Genome medicine · 2026Article
- Mending the Achilles heels of titin in cardiac and musculoskeletal disease.Biophysical reviews · 2026Review
- Next-generation sequencing and comprehensive data reassessment in 263 adult patients with neuromuscular disorders: insights into the gray zone of molecular diagnoses.Journal of neurology · 2024Article
- Structure determination and analysis of titin A-band fibronectin type III domains provides insights for disease-linked variants and protein oligomerisation.Journal of structural biology · 2023Article
- When is an obscurin variant pathogenic? The impact of Arg4344Gln and Arg4444Trp variants on protein-protein interactions and protein stability.Human molecular genetics · 2021Article
- Making sense of missense variants in TTN-related congenital myopathies.Acta neuropathologica · 2021Article
- Patient mutations linked to arrhythmogenic cardiomyopathy enhance calpain-mediated desmoplakin degradation.JCI insight · 2019Article
- Obscurin is a semi-flexible molecule in solution.Protein science : a publication of the Protein Society · 2019Article
- Structural diversity in the atomic resolution 3D fingerprint of the titin M-band segment.PloS one · 2019Article
- TITINdb-a computational tool to assess titin's role as a disease gene.Bioinformatics (Oxford, England) · 2017Article
- Deregulated CaScience advances · 2017Article
- A novel FLNC frameshift and an OBSCN variant in a family with distal muscular dystrophy.PloS one · 2017Article
- Increasing Role of Titin Mutations in Neuromuscular Disorders.Journal of neuromuscular diseases · 2016Review
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Authors and funding
3 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
The giant proteins titin and obscurin are important for sarcomeric organization, stretch response, and sarcomerogenesis in myofibrils. The extreme C-terminus of titin (the M10 domain) binds to the N-terminus of obscurin (the Ig1 domain) in the M-band. The high-resolution structure of human M10 has been solved, along with M10 bound to one of its two known molecular targets, the Ig1 domain of obscurin-like. Multiple M10 mutations are linked to limb-girdle muscular dystrophy type 2J (LGMD2J) and tibial muscular dystrophy (TMD). The effect of the M10 mutations on protein structure and function has not been thoroughly characterized. We have engineered all four of the naturally occurring human M10 missense mutants and biophysically characterized them in vitro. Two of the four mutated constructs are severely misfolded, and cannot bind to the obscurin Ig1 domain. One mutation, H66P, is folded at room temperature but unfolds at 37°C, rendering it binding incompetent. The I57N mutation shows no significant structural, dynamic, or binding differences from the wild-type domain. We suggest that this mutation is not directly responsible for muscle wasting disease, but is instead merely a silent mutation found in symptomatic patients. Understanding the biophysical basis of muscle wasting disease can help streamline potential future treatments.
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