The Desmoplakin Hinge Domain Confers a Reversible Conformational Change in Response to Acute External Force

Abstract

Desmosomes provide mechanical integrity to tissues that experience strain, yet how mechanical force is sensed and distributed within the desmosomal plaque remains poorly understood. Here we identify the hinge within the desmoplakin (DP) head domain is required for repositioning the DP tail in response to acute uniaxial mechanical stretch. This repositioning occurs within 30 seconds of applied stretch and reverses with release, indicating a dynamic reversible switch rather than a stable structural transition. We show this hinge-dependent repositioning correlates with the propagation of mechanical force to the desmosomal cadherins, consistent with the hinge's role in buffering tension at the cadherin interface during mechanical loading. Deletion or shortening of the hinge abolishes the stretch-induced response and compromises desmosome mechanical integrity. The repositioning of the DP tail in the calcium-dependent to hyper-adhesive transition was not impacted by alterations to the hinge, demonstrating that DP repositioning due to acute force or adhesive state is mechanistically distinct. Together, these findings define a reversible, hinge-dependent mechanotransduction pathway through which DP senses and relays mechanical force within the desmosome. This mechanism could act as a mechanical buffer by reducing the impulse of forces on the cadherins, and play a central role in mechanical resilience.