Lst4, the yeast Fnip1/2 orthologue, is a DENN-family protein

Open Biol. 2015 Dec;5(12):150174. doi: 10.1098/rsob.150174.

Abstract

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.

Keywords: BHD syndrome; DENN-family; Fnip1/2; Lst4; Lst7; folliculin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Fungal Proteins / chemistry*
  • Fungal Proteins / metabolism*
  • Kluyveromyces / metabolism*
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / metabolism
  • Vesicular Transport Proteins / chemistry
  • Vesicular Transport Proteins / metabolism

Substances

  • Fungal Proteins
  • LST4 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Vesicular Transport Proteins