Lst4, the yeast Fnip1/2 orthologue, is a DENN-family protein
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The folliculin/Fnip complex has been demonstrated to play a crucial role in the mechanisms underlying Birt–Hogg–Dubé (BHD) syndrome, a rare inherited cancer syndrome. Lst4 has been previously proposed to be the Fnip1/2 orthologue in yeast and therefore a member of the DENN family. In order to confirm this, we solved the crystal structure of the N-terminal region of Lst4 from Kluyveromyces lactis and show it contains a longin domain, the first domain of the full DENN module. Furthermore, we demonstrate that Lst4 through its DENN domain interacts with Lst7, the yeast folliculin orthologue. Like its human counterpart, the Lst7/Lst4 complex relocates to the vacuolar membrane in response to nutrient starvation, most notably in carbon starvation. Finally, we express and purify the recombinant Lst7/Lst4 complex and show that it exists as a 1 : 1 heterodimer in solution. This work confirms the membership of Lst4 and the Fnip proteins in the DENN family, and provides a basis for using the Lst7/Lst4 complex to understand the molecular function of folliculin and its role in the pathogenesis of BHD syndrome.
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The structure of the Kluyveromyces lactis Lst4 N-terminal longin domain revealed a classic longin domain architecture, the first subdomain of the complete DENN.
“The structure revealed a classic longin domain architecture, which is the first subdomain of the complete DENN”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Pacitto et al., 2015
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- Authors
- Pacitto, A., Ascher, D. B., Wong, L. H., Blaszczyk, B. K., Nookala, R. K., Zhang, N., Dokudovskaya, S., Levine, T. P., & Blundell, T. L.
- Affiliations
- University of Cambridge (GB)
- University College London (GB)
- Université Paris-Sud (FR)
- Corresponding author
- Pacitto, Angela
- Blundell, Tom L.
- ORCID
- Venue
- Open Biology
- Publisher
- The Royal Society
- Published
- 2015-12
- Volume
- 5
- Issue
- 12
- Pages
- 150174
- ISSN
- 2046-2441 (ISSN-L)
- PMC
- PMC4703059
- OpenAlex
- W2213367053
- Cited by
- 28
- References
- 48
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 1 · 2021: 4 · 2020: 3 · 2019: 6 · 2018: 3 · 2017: 4 · 2016: 4
- FWCI
- 1.94
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Open Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Funders
- Wellcome Trust
- Myrovlytis Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- folliculin, Birt-Hogg-Dubé syndrome, longin domain, Kluyveromyces lactis, heterodimer, tonoplast, carbon starvation, nutrient deprivation, crystal structure
- MeSH terms
- Fungal Proteins, Kluyveromyces, Protein Structure, Secondary, Protein Structure, Tertiary, Saccharomyces cerevisiae Proteins, Vesicular Transport Proteins
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