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Published on: November 10, 2021
Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer
Ravi K Nookala1, Lars Langemeyer, Angela Pacitto
1Department of Biochemistry , University of Cambridge, Sanger Building, 80 Tennis Court Road, Cambridge CB2 1GA, UK. rn229@cam.ac.uk
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.
Insights
Mutations in the tumor suppressor folliculin cause cancer. Researchers determined its structure and found it acts as a Rab guanine nucleotide exchange factor (GEF), revealing a new role in cell regulation.
Area of Science:
- Molecular Biology
- Structural Biology
- Oncology
Background:
- Mutations in the renal tumor suppressor protein, folliculin, are linked to various cancers, including renal cell carcinoma.
- Folliculin's interaction with AMP-activated kinase and the mTOR pathway suggests a role in cell growth regulation.
- Most cancer-associated mutations involve a truncated carboxy-terminal domain, highlighting its importance in tumor suppression.
Purpose of the Study:
- To elucidate the structural and functional characteristics of the folliculin carboxy-terminal domain.
- To investigate the potential relationship between folliculin and known protein families involved in cellular processes.
Main Methods:
- X-ray crystallography was used to determine the three-dimensional structure of the folliculin carboxy-terminal domain.
- Biochemical assays were performed to assess the functional activity of the folliculin protein.
Main Results:
- The crystal structure revealed that the folliculin carboxy-terminal domain is distantly related to differentially expressed in normal cells and neoplasia (DENN) domain proteins.
- Biochemical analysis demonstrated that folliculin possesses guanine nucleotide exchange factor (GEF) activity.
- These findings suggest folliculin functions as a Rab GEF.
Conclusions:
- Folliculin is a distantly related member of the Rab guanine nucleotide exchange factor family.
- The GEF activity of folliculin provides new insights into its tumor suppressor function and cellular regulation mechanisms.
- Understanding folliculin's role as a Rab GEF may open new avenues for cancer therapy development.
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