SMCR8-C9orf72 complex subunit (SMCR8)

SMCR8-C9orf72 complex subunit (SMCR8) is a protein that forms a stable heterotrimeric complex with C9ORF72 and WDR41, primarily regulating autophagy, membrane trafficking, and lysosomal homeostasis[1][3][6]. SMCR8 contains Longin and DENN domains, consistent with its function as a GTPase-activating protein (GAP) and guanine nucleotide exchange factor (GEF) for small GTPases, notably RAB and ARF family proteins[1][3][5][8]. It has a central role in modulating the activation state of RAB8A, RAB11A, and ARF1 through its DENN domain and a conserved arginine finger, regulating processes like autophagosome maturation and mTORC1 signaling[1][8]. Mutations or loss of SMCR8 and its associated complex have been linked to neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), as well as lysosomal and immune system dysfunction[2][4][5][6]. SMCR8 is also associated with protein ubiquitination pathways, interacts with chromatin in the nucleus, and acts as a negative regulator of lysosomal exocytosis[5][7][9]. No direct drug interactions are known to date.

Other names

Guanine nucleotide exchange protein SMCR8DENND8ASmith-Magenis syndrome chromosomal region candidate gene 8 proteinFLJ34716SMCR8-C9orf72 complex subunitSmith-Magenis syndrome chromosome region, candidate 8

Regulates small GTPase activity (GAP activity for Rab8a, Rab11a, ARF1) GEF activity for RAB proteins (RAB8A, RAB39B) Regulation of autophagosome maturation Regulation of mTORC1 pathway via modulation of lysosomal signaling