NDLI: Identification of an N-terminal inhibitory extension as the primary mechanosensory regulator of twitchin kinase

Content Provider	PubMed Central
Author	Von, Castelmur Eleonore Johan, Strümpfer Franke, Barbara Bogomolovas, Julijus Barbieri, Sonia Hiroshi, Qadota Konarev, Petr V. Svergun, Dmitri I. Siegfried, Labeit Benian, Guy M. Schulten, Klaus Mayans, Olga
Abstract	Titin-like kinases are an important class of cytoskeletal kinases that intervene in the response of muscle to mechanical stimulation, being central to myofibril homeostasis and development. These kinases exist in autoinhibited states and, allegedly, become activated during muscle activity by the elastic unfolding of a C-terminal regulatory segment (CRD). However, this mechano-activation model remains controversial. Here we explore the structural, catalytic, and tensile properties of the multidomain kinase region of Caenorhabditis elegans twitchin (Fn31-Nlinker-kinase-CRD-Ig26) using X-ray crystallography, small angle X-ray scattering, molecular dynamics simulations, and catalytic assays. This work uncovers the existence of an inhibitory segment that flanks the kinase N-terminally (N-linker) and that acts synergistically with the canonical CRD tail to silence catalysis. The N-linker region has high mechanical lability and acts as the primary stretch-sensor in twitchin kinase, while the CRD is poorly responsive to pulling forces. This poor response suggests that the CRD is not a generic mechanosensor in this kinase family. Instead, the CRD is shown here to be permissive to catalysis and might protect the kinase active site against mechanical damage. Thus, we put forward a regulatory model where kinase inhibition results from the combined action of both N- and C-terminal tails, but only the N-terminal extension undergoes mechanical removal, thereby affording partial activation. Further, we compare invertebrate and vertebrate titin-like kinases and identify variations in the regulatory segments that suggest a mechanical speciation of these kinase classes.
Related Links	http://dx.doi.org/10.1073/pnas.1200697109
Ending Page	13613
Page Count	6
Starting Page	13608
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	34
Volume Number	109
Language	English
Publisher	National Academy of Sciences
Publisher Date	2012-08-21
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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