guanosine-diphosphate and Kidney-Neoplasms

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 probably a distantly related member of this class of Rab GEFs.

Topics: Amino Acid Sequence; Carcinoma, Renal Cell; Crystallography, X-Ray; Death Domain Receptor Signaling Adaptor Proteins; Electrophoresis, Polyacrylamide Gel; Guanine Nucleotide Exchange Factors; Guanosine Diphosphate; Guanosine Triphosphate; Humans; Kidney Neoplasms; Models, Molecular; Molecular Sequence Data; Mutation; Protein Structure, Secondary; Protein Structure, Tertiary; Proto-Oncogene Proteins; Sequence Homology, Amino Acid; Tumor Suppressor Proteins