Fungal PDR transporters: Phylogeny, topology, motifs and function

Area of Science:

• Biochemistry
• Molecular Biology
• Mycology

Background:

• Pleiotropic drug resistance (PDR) efflux pumps, part of the ATP-binding cassette (ABC) transporter superfamily, are frequently overexpressed in multidrug-resistant organisms.
• This overexpression is a significant factor contributing to the challenge of treating infections caused by multidrug-resistant fungal pathogens.

Purpose of the Study:

• To conduct a comprehensive phylogenetic analysis of full-size PDR proteins (Pdrps) across diverse fungal species.
• To identify evolutionary relationships and structural characteristics of Pdrps that may inform our understanding of multidrug resistance mechanisms.

Main Methods:

• Phylogenetic analysis of 349 full-size Pdrps from 55 fungal species.
• Comparative analysis of protein structures, including nucleotide-binding domains (NBDs) and transmembrane domains (TMDs), and their arrangement.
• Identification and analysis of conserved and unique structural elements and motifs.

Main Results:

• Nine distinct protein clusters (A-G, H1a/H1b, H2) were identified among the analyzed Pdrps.
• Full-size fungal and plant Pdrps exhibit a duplicated NBD-TMD topology, characteristic of the ABCG family.
• Asymmetry was observed in NBDs and extracellular loops, with cluster F members showing the highest symmetry, suggesting a potential ancestral link.

Conclusions:

• The study provides a detailed evolutionary framework for fungal Pdrps, highlighting conserved and divergent structural features.
• Understanding these structural variations, particularly in symmetric members like cluster F, could offer insights into the ancestral PDR transporter and its functional evolution.
• The identification of unique structural elements and PDR-specific motifs lays the groundwork for future research into targeted strategies against fungal multidrug resistance.