The LUFS domain, its transcriptional regulator proteins, and drug resistance in the fungal pathogen Candida auris

Abstract

The LUFS domain (LUG/LUH, Flo8, single-strand DNA-binding protein [SSBP]) is a well-conserved and apparently ancient region found in diverse proteins and taxa. This domain, which has as its most obvious structural feature a series of three helices, has been identified in transcriptional regulator proteins of animals, plants, and fungi. Recently, in these pages (Wang et al., Protein Sci., 2019, 28:788-793), the first crystal structure of a LUFS domain was reported, for the human SSBP2, a transcriptional repressor. We briefly address how the new insights into LUFS structures might contribute to a better understanding of an important transcriptional activator of yeasts that contains the LUFS domain, Flo8, and consider how a focus on the LUFS domain and its variation could help us to understand etiologies of drug resistance in a recently emerged pathogenic fungus, Candida auris.

Keywords: Candida; LUFS domain; activation and repression domains; amphotericin B; antifungal resistance mechanisms; filamentation in fungi; flocculence; single nucleotide polymorphisms; transcription factors; whole-genome sequence comparisons.

Figure 1

Structural views of LUFS domains and their helix and interhelix linker regions in (a) the homotetramer formed by four copies of the human SSBR2 protein (PDB accession number 6IWV2), with broad red arrows pointing to the linker regions between helices α2 and α3 in each monomer, and in (b) the corresponding, possible homotetramer of the Flo8 protein of Candida auris as modeled from the primary sequence without (top) and with (bottom) the serine‐to‐asparagine mutation (black arrows) associated with AmB resistance in Colombia. Modeling was performed by SWISS‐MODEL,23 using the crystal structure of SSBR2 as a template. The views are cartoons rendered by NGL Viewer24 on the RCSB PDB25 and SWISS‐MODEL web servers

Figure 2

Sequence views of LUFS domains and their helix and interhelix linker regions and, for comparison, chosen sequences involved in activation of transcription of eukaryotic genes. (a) Helix‐anchored alignment of LUFS‐containing protein sequences from human (SSBP2/3/4), a plant (Arabidopsis thaliana LEUNIG/LUG/LUH), and fungi (Flo8 from Candida albicans, C. glabrata, C. auris, and S. cerevisiae). Inset shows detail of corresponding insert segments for C. auris and C. intermedia. Tracks below amino acid sequences indicate negatively charged residues (−; D or E) and serine–threonine clusters (s; S or T) with or without nearby prolines that may have a stabilizing role (blue amino acids21). Black arrows point to the S (serine) that is mutated to N (asparagine) in the Colombian AmB‐resistant clade of C. auris (see text). (b) Sequences of the transcriptional activation domain of the S. cerevisiae transcription factor GCN4 (26 pp. 182–183), of an N‐terminal segment of the potentiation domain in the human metal regulatory transcription factor 1 (MTF1) that when deleted reduces transcriptional efficiency by roughly half,27, 28 with the orthologous sequence in the pufferfish Fugu rubripes 29 showing often larger negative clusters, and of the repeats in the C‐terminal domain of the RPB1 subunit of human RNA polymerase II (26 p., 216).21 Tracks below the sequences are as in (a)