Nonmuscle myosin IIA dynamically guides regulatory light chain phosphorylation and assembly of nonmuscle myosin IIB |
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Affiliation: | 1. Zoological Institute, Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany;2. Institute of Functional Interfaces (IFG), Karlsruhe Institute of Technology (KIT), 76131 Karlsruhe, Germany;3. Institute for Theoretical Physics, University of Heidelberg, Philosophenweg 19, 69120 Heidelberg, Germany;4. BioQuant-Center for Quantitative Biology, University of Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany;5. Institute for Biological and Chemical Systems - Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), 76344 Karlsruhe, Germany |
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Abstract: | Nonmuscle myosin II minifilaments have emerged as central elements for force generation and mechanosensing by mammalian cells. Each minifilament can have a different composition and activity due to the existence of the three nonmuscle myosin II paralogs A, B and C and their respective phosphorylation pattern. We have used CRISPR/Cas9-based knockout cells, quantitative image analysis and mathematical modeling to dissect the dynamic processes that control the formation and activity of heterotypic minifilaments and found a strong asymmetry between paralogs A and B. Loss of NM IIA completely abrogates regulatory light chain phosphorylation and reduces the level of assembled NM IIB. Activated NM IIB preferentially co-localizes with pre-formed NM IIA minifilaments and stabilizes the filament in a force-dependent mechanism. NM IIC is only weakly coupled to these processes. We conclude that NM IIA and B play clearly defined complementary roles during assembly of functional minifilaments. NM IIA is responsible for the formation of nascent pioneer minifilaments. NM IIB incorporates into these and acts as a clutch that limits the force output to prevent excessive NM IIA activity. Together these two paralogs form a balanced system for regulated force generation. |
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Keywords: | Mechanobiology Cellular force generation Actomyosin Nonmuscle myosin II Minifilaments Paralogs |
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