The Z-disc protein α-actinin-2 forms a force-activated, directional bond with F-actin

The Z-disc protein α-actinin-2 forms a force-activated, directional bond with F-actin | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The Z-disc protein α-actinin-2 forms a force-activated, directional bond with F-actin Alexander Dunn, Christopher Marang, Brian Zhong This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8031513/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Force generation in the heart relies on sarcomeres in which myosin II contracts antiparallel arrays of F-actin. Sarcomeres are linked at Z-discs, where the protein α-actinin-2 crosslinks antiparallel F-actin from adjoining sarcomeres and recruits signaling proteins that regulate cardiomyocyte growth. How Z-discs self-assemble and transduce mechanical signals remains unclear. Using optical trap assays, we find that the bond between α-actinin-2 and F-actin selectively strengthens under load applied toward the pointed, (–) end, the direction of myosin force production, whereas binding is dramatically attenuated when load is oriented toward the filament (+) end. Mutations that cause hypertrophic cardiomyopathy (G111V, A119T, T247M) weaken this bond and disrupt directionality, defects that are amplified when multiple α-actinin-2 work together to anchor F-actin against (–)-end directed loads. We further demonstrate that anchoring by wild-type α-actinin-2 assists cardiac myosin II in generating force against an external load, while A119T α-actinin-2 blocks myosin force production. The directional interaction between α-actinin-2 and F-actin offers a plausible mechanism by which the antiparallel organization of actin filaments at the Z-disc, and thereby sarcomeric order as a whole, can emerge spontaneously in response to myosin-generated force. Our data likewise implicate α-actinin-2 as a key mechanosensor in the cardiac sarcomere. Biological sciences/Biophysics Biological sciences/Physiology/Cardiovascular biology Full Text Additional Declarations There is NO Competing Interest. Supplementary Files supplementFINAL.pdf Supplementary Information and Materials Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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