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	Ravi K Nookala, Lars Langemeyer, Angela Pacitto, Bernardo Ochoa-Montaño, Jane C Donaldson, Beata K Blaszczyk, Dimitri Y Chirgadze, Francis A Barr, J Fernando Bazan, Tom L Blundell
Journal	Open biology (Open Biol) Vol. 2 Issue 8 Pg. 120071 (Aug 2012) ISSN: 2046-2441 [Electronic] England
PMID	22977732 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	DENND1B protein, human Death Domain Receptor Signaling Adaptor Proteins FLCN protein, human Guanine Nucleotide Exchange Factors Proto-Oncogene Proteins Tumor Suppressor Proteins Guanosine Diphosphate Guanosine Triphosphate
Topics	Amino Acid Sequence Carcinoma, Renal Cell (genetics, metabolism) Crystallography, X-Ray Death Domain Receptor Signaling Adaptor Proteins (chemistry, genetics, metabolism) Electrophoresis, Polyacrylamide Gel Guanine Nucleotide Exchange Factors (chemistry, genetics, metabolism) Guanosine Diphosphate (metabolism) Guanosine Triphosphate (metabolism) Humans Kidney Neoplasms (genetics, metabolism) Models, Molecular Molecular Sequence Data Mutation Protein Structure, Secondary Protein Structure, Tertiary Proto-Oncogene Proteins (chemistry, metabolism) Sequence Homology, Amino Acid Tumor Suppressor Proteins (chemistry, metabolism)

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