Cryo-EM structural study of the complex between ACTN2 D893C HD and ZASP R16C

The sarcomere is the smallest repeating unit of muscle fibers. Its structure is maintained by the Z-disk, an ultrastructure of 60+ proteins which are also involved in signaling processes such as mechanotransduction and autophagy turnover in muscles. The primary component of the Z-disk is alpha-actinin 2, responsible for crosslinking actin and titin filaments. One of its binding partners is ZASP, a protein which is essential for the structural integrity of the sarcomere. One interaction site between the ZASP PDZ and ACTN2 EF-34 is known, but there is evidence to indicate that ZASP motif (ZM), downstream of the PDZ domain, might interact with alpha-actinin’s spectrin repeats (SRs). However, as the ZM motif is contained within an intrinsically disordered region (ZASP IDR), the interaction of this region with alpha-actinin, as well as the structure of both interaction sites, have so far remained elusive.