Neurodevelopmental disorder mutations in the exchange factor DENN/MADD disrupt activation of Rab GTPases.

ABSTRACT: DENN/MADD (mitogen-activated protein kinase-activating death domain), a differentially expressed in normal and neoplastic cells (DENN) domain-containing protein functions in membrane trafficking. DENN domain-bearing proteins have guanine nucleotide exchange factor activity toward Rab GTPases. Here, we identify Rab GTPase substrates for DENN/MADD using a cell-based assay involving DENN domain-mediated recruitment of Rab substrates to mitochondria. We confirmed known interactions of DENN/MADD with Rab3A, Rab3B, Rab3C, Rab3D, and Rab27B and identified four new potential substrates, Rab8B, Rab15, Rab26, and Rab37, results confirmed with biochemical experiments. Mutations in the DENN domain of DENN/MADD result in diverse pathophysiological manifestations, ranging from predominant neurological d

SUBMITTER: Khan M 

PROVIDER: S-EPMC12495445 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature