A composite motif in calcimembrin/C16orf74 dictates multimeric dephosphorylation by calcineurin.

ABSTRACT: Calcineurin, the Ca²⁺/calmodulin-activated protein phosphatase, recognizes substrates and regulators via short linear motifs, PxIxIT and LxVP, which dock to distinct sites on calcineurin to determine enzyme distribution and catalysis, respectively. Calcimembrin/C16orf74 (CLMB), an intrinsically disordered microprotein whose expression correlates with poor cancer outcomes, targets calcineurin to membranes where it may promote oncogenesis by shaping calcineurin signaling. We show that CLMB associates with membranes via lipidation, i.e., N-myristoylation and reversible S-acylation. Furthermore, CLMB contains an unusual composite 'LxVPxIxIT' motif, that binds the PxIxIT-docking site on calcineurin with extraordinarily high affinity when phosphorylated, ³³LDVPDIIITPP(p)T

SUBMITTER: Bradburn DA 

PROVIDER: S-EPMC12612047 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature