DHHC

DHHC refers to a family of protein acyltransferases characterized by a conserved DHHC motif (Asp-His-His-Cys) within a cysteine-rich domain. These are integral membrane enzymes that catalyze S-palmitoylation, attaching palmitoyl groups from palmitoyl-CoA to cysteine residues on substrate proteins.

The mechanism involves formation of a palmitoyl-enzyme intermediate and transfer of the palmitoyl group to substrate cysteines, creating a reversible thioester linkage. Palmitoylation influences protein membrane association, subcellular localization, stability, and signaling. The modification is dynamic and reversible by acyl-protein thioesterases such as APT1 and APT2, allowing rapid cycling of palmitoylation states in response to cellular cues.

Architecturally, most DHHC proteins contain four to six transmembrane segments, with the DHHC-CRD region facing the cytosol to form the catalytic core. The human DHHC family is large, comprising around two dozen members commonly designated ZDHHC1 through ZDHHC24, though exact membership varies by annotation.

Localization and roles vary among family members. DHHC proteins reside in the endoplasmic reticulum, Golgi apparatus, plasma membrane, and other cellular compartments, where they regulate trafficking and function of a wide range of client proteins, including receptors, ion channels, and signaling proteins. In neurons, several DHHC enzymes contribute to synaptic development and plasticity.

Clinical relevance is indicated by associations between altered DHHC expression or mutations and diseases such as neurodevelopmental disorders and cancer, reflecting the widespread importance of palmitoylation in cell biology. See also S-palmitoylation, acyl-protein thioesterases, and the ZDHHC family.