biostudies-literatureNookala RKWellcome Trust120071https://www.ebi.ac.uk/biostudies/studies/S-EPMC3438538biostudies-literatureUnknown2(8)Mutations in the renal tumour suppressor protein, folliculin, lead to proliferative skin lesions, lung complications and renal cell carcinoma. Folliculin has been reported to interact with AMP-activated kinase, a key component of the mammalian target of rapamycin pathway. Most cancer-causing mutations lead to a carboxy-terminal truncation of folliculin, pointing to a functional importance of this domain in tumour suppression. We present here the crystal structure of folliculin carboxy-terminal domain and demonstrate that it is distantly related to differentially expressed in normal cells and neoplasia (DENN) domain proteins, a family of Rab guanine nucleotide exchange factors (GEFs). Using biochemical analysis, we show that folliculin has GEF activity, indicating that folliculin is probablOpen biologyCrystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer.PMC3438538097769/Z/11/Z097769Barr FAChirgadze DYBlundell TLBazan JFBlaszczyk BKPacitto AOchoa-Montano BDonaldson JCNookala RKLangemeyer LfalseCrystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer.Mutations in the renal tumour suppressor protein, folliculin, lead to proliferative skin lesions, lung complications and renal cell carcinoma. Folliculin has been reported to interact with AMP-activated kinase, a key component of the mammalian target of rapamycin pathway. Most cancer-causing mutations lead to a carboxy-terminal truncation of folliculin, pointing to a functional importance of this domain in tumour suppression. We present here the crystal structure of folliculin carboxy-terminal domain and demonstrate that it is distantly related to differentially expressed in normal cells and neoplasia (DENN) domain proteins, a family of Rab guanine nucleotide exchange factors (GEFs). Using biochemical analysis, we show that folliculin has GEF activity, indicating that folliculin is probabl2012-01-01T00:00:00Z2012 Aug2026-04-17T15:04:08.435Z2019-03-27T00:57:48ZS-EPMC34385382297773210.1098/rsob.120071