Increasing evidence of mechanical force as a functional regulator in smooth muscle myosin light chain kinase
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 act...
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doaj-0909c6d931614472b45523df1eba52f62021-05-05T13:36:26ZengeLife Sciences Publications LtdeLife2050-084X2017-07-01610.7554/eLife.26473Increasing evidence of mechanical force as a functional regulator in smooth muscle myosin light chain kinaseFabian Baumann0Magnus Sebastian Bauer1https://orcid.org/0000-0003-1357-2852Martin Rees2Alexander Alexandrovich3Mathias Gautel4Diana Angela Pippig5Hermann Eduard Gaub6https://orcid.org/0000-0002-4220-6088Chair for Applied Physics and Center for Nanoscience, Ludwig-Maximilians-Universität München, Munich, GermanyChair for Applied Physics and Center for Nanoscience, Ludwig-Maximilians-Universität München, Munich, Germany; Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Munich, GermanyRandall Division of Cell and Molecular Biophysics, King's College London BHF Centre of Research Excellence, London, United KingdomRandall Division of Cell and Molecular Biophysics, King's College London BHF Centre of Research Excellence, London, United KingdomRandall Division of Cell and Molecular Biophysics, King's College London BHF Centre of Research Excellence, London, United KingdomChair for Applied Physics and Center for Nanoscience, Ludwig-Maximilians-Universität München, Munich, GermanyChair for Applied Physics and Center for Nanoscience, Ludwig-Maximilians-Universität München, Munich, GermanyMechanosensitive 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.https://elifesciences.org/articles/26473smooth muscle myosin light chain kinaseforce-activationcytoskeletonauto-inhibitionsingle-molecule force spectroscopyatomic force microscopy |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Fabian Baumann Magnus Sebastian Bauer Martin Rees Alexander Alexandrovich Mathias Gautel Diana Angela Pippig Hermann Eduard Gaub |
spellingShingle |
Fabian Baumann Magnus Sebastian Bauer Martin Rees Alexander Alexandrovich Mathias Gautel Diana Angela Pippig Hermann Eduard Gaub Increasing evidence of mechanical force as a functional regulator in smooth muscle myosin light chain kinase eLife smooth muscle myosin light chain kinase force-activation cytoskeleton auto-inhibition single-molecule force spectroscopy atomic force microscopy |
author_facet |
Fabian Baumann Magnus Sebastian Bauer Martin Rees Alexander Alexandrovich Mathias Gautel Diana Angela Pippig Hermann Eduard Gaub |
author_sort |
Fabian Baumann |
title |
Increasing evidence of mechanical force as a functional regulator in smooth muscle myosin light chain kinase |
title_short |
Increasing evidence of mechanical force as a functional regulator in smooth muscle myosin light chain kinase |
title_full |
Increasing evidence of mechanical force as a functional regulator in smooth muscle myosin light chain kinase |
title_fullStr |
Increasing evidence of mechanical force as a functional regulator in smooth muscle myosin light chain kinase |
title_full_unstemmed |
Increasing evidence of mechanical force as a functional regulator in smooth muscle myosin light chain kinase |
title_sort |
increasing evidence of mechanical force as a functional regulator in smooth muscle myosin light chain kinase |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2017-07-01 |
description |
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. |
topic |
smooth muscle myosin light chain kinase force-activation cytoskeleton auto-inhibition single-molecule force spectroscopy atomic force microscopy |
url |
https://elifesciences.org/articles/26473 |
work_keys_str_mv |
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