CD38–ZDHHC9 protein–protein interface (CD38–ZDHHC9 PPI)

The CD38–ZDHHC9 protein–protein interface is a critical regulatory site where the palmitoyl acyltransferase ZDHHC9 interacts with and palmitoylates the ectoenzyme CD38 (UniProt P28907, Q9Y397). This post-translational modification is essential for the stabilization of CD38 and its proper localization to the plasma membrane and lipid rafts, where it functions as a major NAD+ glycohydrolase and a signaling molecule (Leukemia, 2023, PMID: 37468541). In diseases such as Multiple Myeloma, ZDHHC9-mediated palmitoylation prevents the lysosomal degradation of CD38, maintaining high surface levels that contribute to tumor cell survival and immune evasion. Targeting this interface represents a novel therapeutic approach to downregulate CD38 expression, which could enhance the efficacy of existing CD38-targeted therapies like daratumumab or serve as a standalone strategy to disrupt cancer metabolism. Small molecule inhibitors or peptides designed to block this specific interaction are currently being explored in preclinical research to overcome resistance in hematological malignancies.

Other names

CD38-ZDHHC9 complexCD38 palmitoylation interfaceZDHHC9-CD38 interaction

Disruption of the interaction between ZDHHC9 and CD38 to inhibit CD38 palmitoylation, leading to reduced CD38 protein stability, increased degradation, and decreased cell surface expression.