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

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.