Histidine-rich coiled-coils promote zinc-dependent self-assembly and curing of porous mussel glues.

Challenging to engineer in synthetic glues, wet adhesion is critical for many technical and biomedical applications. Mussels, however, have evolved underwater glues that adhere effectively onto slippery seashore surfaces. Past research on mussel adhesion highlights the importance of the post-translationally modified amino acid 3,4-dihydroxyphenylalanine (DOPA), found in abundance in mussel glue proteins. Yet, DOPA alone is insufficient to match native adhesion in synthetic mimics. Here, we provide evidence that a previously uncharacterized histidine-rich protein (mefp-12) plays a crucial role in the formation, curing, and performance of mussel glue. Biochemical analysis localizes mefp-12 within vesicles of the mussel glue secretory glands, while AI-assisted modeling of its sequence predicts Zn-stabilized coiled coil conformation and several domains resembling zinc-finger motifs. In vitro investigation of a His-rich α-helical peptide from mefp-12 shows Zn- and pH-dependent liquid-liquid phase separation (LLPS), coalescence, and spreading over the substrate. Exposure to seawater pH induces subsequent self-organization of the fluid condensates into solid nanoporous networks resembling the structure of the native mussel glue. Based on these findings we gain a deeper mechanistic understanding of mussel glue formation and function that challenges the dominant DOPA-centric paradigm, providing inspiration for design of bio-inspired wet adhesives.