Biophysical characterization of naturally occurring titin M10 mutations

Protein Science : a Publication of the Protein Society
Michael W RudloffNathan T Wright

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. Underst...Continue Reading

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Citations

May 24, 2015·FEBS Letters·Tracy A CaldwellNathan T Wright
Sep 17, 2015·Biomolecular NMR Assignments·Joshua E TempleNathan T Wright
Oct 28, 2017·Bioinformatics·Anna LaddachFranca Fraternali
Jan 23, 2019·Protein Science : a Publication of the Protein Society·Jacob A WhitleyNathan T Wright
Jan 27, 2019·Expert Review of Proteomics·Sandra MurphyKay Ohlendieck
Jun 21, 2017·Science Advances·Li-Yen R HuAikaterini Kontrogianni-Konstantopoulos
Dec 20, 2019·PloS One·Spyros D ChatziefthimiouMatthias Wilmanns
Apr 17, 2015·Human Molecular Genetics·Karine ChartonBjarne Udd
Jan 16, 2021·Acta Neuropathologica·Martin ReesMathias Gautel

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