title: Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer.
abstract: 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.
authors.affiliation: Department of Biochemistry , University of Cambridge, Sanger Building, 80 Tennis Court Road, Cambridge CB2 1GA, UK. rn229@cam.ac.uk
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Nookala
authors.forename: Lars
authors.initials: L
authors.lastname: Langemeyer
authors.forename: Angela
authors.initials: A
authors.lastname: Pacitto
authors.forename: Bernardo
authors.initials: B
authors.lastname: Ochoa-Montaño
authors.forename: Jane C
authors.initials: JC
authors.lastname: Donaldson
authors.forename: Beata K
authors.initials: BK
authors.lastname: Blaszczyk
authors.forename: Dimitri Y
authors.initials: DY
authors.lastname: Chirgadze
authors.forename: Francis A
authors.initials: FA
authors.lastname: Barr
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Bazan
authors.forename: Tom L
authors.initials: TL
authors.lastname: Blundell
mesh_terms: D000595:Amino Acid Sequence; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: C546321:DENND1B protein, human; D053418:Death Domain Receptor Signaling Adaptor Proteins; C476078:FLCN protein, human; D020662:Guanine Nucleotide Exchange Factors; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate