TCB Publications - Abstract

Eleonore von Castelmur, Johan Strümpfer, Barbara Franke, Julijus Bogomolovas, Sonia Barbieri, Hiroshi Qadota, Petr V. Konarev, Dmitri I. Svergun, Siegfried Labeit, Guy M. Benian, Klaus Schulten, and Olga Mayans. Identification of an N-terminal inhibitory extension as the primary mechanosensory regulator of twitchin kinase. Proceedings of the National Academy of Sciences, USA, 109:13608-13613, 2012. (PMC: 3427058)

CAST2012 Titin-like kinases are central to the homeostatic regulation of muscle and are proposed to act as sensors of mechanical signals in the sarcoskeleton. These kinases exist in autoinhibited states and appear to be activated by elastic deformations of their regulatory segments during muscle activity. However, mechano-activation and its mechanistic principles remain controversial. Here, we explore the structural, catalytic and tensile properties of C. elegans twitchin kinase (domains Fn$^{31}$-Nlinker-kinase-CRD- Ig$^{26}$) using X-ray crystallography, SAXS, SMD simulations and catalytic assays. We identify the conserved Nlinker region as an instrasteric inhibitor of catalysis and as the primary mechanosensory region in the ensemble. In contrast, the canonical C-terminal inhibitory tail, CRD, is only partly dislodged by stretch. It remains attached to the kinase, protecting the active site from mechanical damage but being permissive to catalysis. Catalytic silencing requires the synergistic action of Nlinker and CRD segments. We discuss whether force alone can fully activate these kinases and propose that variations in NLinker and CRD regions underlie their mechanical speciation across the muscle biodiversity.

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