Increasing evidence of mechanical force as a functional regulator in smooth muscle myosin light chain kinase

Author:

Baumann Fabian1,Bauer Magnus Sebastian12ORCID,Rees Martin3,Alexandrovich Alexander3,Gautel Mathias3,Pippig Diana Angela1,Gaub Hermann Eduard1ORCID

Affiliation:

1. Chair for Applied Physics and Center for Nanoscience, Ludwig-Maximilians-Universität München, Munich, Germany

2. Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Munich, Germany

3. Randall Division of Cell and Molecular Biophysics, King's College London BHF Centre of Research Excellence, London, United Kingdom

Abstract

Mechanosensitive proteins are key players in cytoskeletal remodeling, muscle contraction, cell migration and differentiation processes. Smooth muscle myosin light chain kinase (smMLCK) is a member of a diverse group of serine/threonine kinases that feature cytoskeletal association. Its catalytic activity is triggered by a conformational change upon Ca2+/calmodulin (Ca2+/CaM) binding. Due to its significant homology with the force-activated titin kinase, smMLCK is suspected to be also regulatable by mechanical stress. In this study, a CaM-independent activation mechanism for smMLCK by mechanical release of the inhibitory elements is investigated via high throughput AFM single-molecule force spectroscopy. The characteristic pattern of transitions between different smMLCK states and their variations in the presence of different substrates and ligands are presented. Interaction between kinase domain and regulatory light chain (RLC) substrate is identified in the absence of CaM, indicating restored substrate-binding capability due to mechanically induced removal of the auto-inhibitory regulatory region.

Funder

Sonderforschungsbereich

European Commission

Medical Research Council

British Heart Foundation

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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