Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer
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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.
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The crystal structure of the human FLCN C-terminal DENN domain revealed the molecular structure of the core c-DENN and downstream d-DENN subdomains.
“The crystal structure of the human FLCN C-terminal DENN domain (Fig. S3B) revealed the molecular structure of the core, or c-DENN, and downstream (d-)DENN subdomains (Nookala et al., 2012).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Nookala et al., 2012
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- Authors
- Nookala, R. K., Langemeyer, L., Pacitto, A., Ochoa-Montaño, B., Donaldson, J. C., Blaszczyk, B. K., Chirgadze, D. Y., Barr, F. A., Bazan, J. F., & Blundell, T. L.
- Affiliations
- University of Cambridge (GB)
- University of Oxford (GB)
- Department of Biochemistry, University of Cambridge, Sanger Building, 80 Tennis Court Road, Cambridge CB2 1GA, UK
- NeuroScience, Inc., #373, 280th St., Osceola, WI 54020, USA
- Corresponding author
- Nookala, Ravi K.
- Venue
- Open Biology
- Publisher
- The Royal Society
- Published
- 2012-08
- Volume
- 2
- Issue
- 8
- Pages
- 120071
- ISSN
- 2046-2441 (ISSN-L)
- PMC
- PMC3438538
- OpenAlex
- W2086327073
- Cited by
- 106
- References
- 38
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 9 · 2020: 11 · 2019: 8 · 2018: 13 · 2017: 7 · 2016: 15 · 2015: 9 · 2014: 8 · 2013: 12 · 2012: 5
- FWCI
- 8.76
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Open Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Wellcome Trust (097769/Z/11/Z, 097769)
- King's College London
- Department of Biochemistry, University of Cambridge
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- folliculin, C-terminal domain, crystal structure, AMPK, mTOR signaling, renal cell carcinoma, tumor suppression, C-terminal truncation
- MeSH terms
- Amino Acid Sequence, Carcinoma, Renal Cell, Electrophoresis, Polyacrylamide Gel, Guanosine Diphosphate, Guanosine Triphosphate, Humans, Kidney Neoplasms, Models, Molecular, Molecular Sequence Data, Mutation, Proto-Oncogene Proteins, Sequence Homology, Amino Acid, Protein Structure, Secondary, Protein Structure, Tertiary, Crystallography, X-Ray, Guanine Nucleotide Exchange Factors, Tumor Suppressor Proteins, Death Domain Receptor Signaling Adaptor Proteins
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