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.
Keywords:
Birt–Hogg–Dubé syndrome; DENN; folliculin; renal cell carcinoma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Carcinoma, Renal Cell / genetics
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Carcinoma, Renal Cell / metabolism
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Crystallography, X-Ray
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Death Domain Receptor Signaling Adaptor Proteins / chemistry*
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Death Domain Receptor Signaling Adaptor Proteins / genetics
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Death Domain Receptor Signaling Adaptor Proteins / metabolism
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Electrophoresis, Polyacrylamide Gel
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Guanine Nucleotide Exchange Factors / chemistry*
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Guanine Nucleotide Exchange Factors / genetics
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Guanine Nucleotide Exchange Factors / metabolism
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Guanosine Diphosphate / metabolism
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Guanosine Triphosphate / metabolism
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Humans
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Kidney Neoplasms / genetics
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Kidney Neoplasms / metabolism
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Models, Molecular
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Molecular Sequence Data
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Mutation
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / metabolism
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Sequence Homology, Amino Acid
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Tumor Suppressor Proteins / chemistry
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Tumor Suppressor Proteins / metabolism
Substances
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DENND1B protein, human
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Death Domain Receptor Signaling Adaptor Proteins
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FLCN protein, human
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Guanine Nucleotide Exchange Factors
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Proto-Oncogene Proteins
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Tumor Suppressor Proteins
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Guanosine Diphosphate
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Guanosine Triphosphate