RND transporters in the living world

Abstract

Transporters of the RND superfamily are well-known as the major drug efflux pumps of Gram-negative bacteria. However, they are widespread in organisms ranging from Archaea to Eukaryotes, and perform diverse functions. This review gives a brief overview of these diverse members of the superfamily with emphasis on their structure and functions.

Keywords: Phylogeny; Quaternary structure; Superfamily.

Fig. 1

Current view of the phylogenetic relationship among members of the RND superfamily. From Yen et al [1].

Fig. 2

The structure of T. thermophilus SecDF. The upper panel shows the X-ray crystallographic structure. The lower panel shows a hypothetical mechanism by which SecDF enhances the efficiency of secretion through the SecYEG translocon, by pulling the nascent polypeptide via the relative translocation of P1 head vs. P1 base subdomains. From [4].

Fig. 3

Crystallographic structure of an HAE1 family RND transporter AcrB (at right) compared with other classes of efflux transporters belonging to ABC, major facilitator (MF), MATE and SMR families. The bound ligands are shown as purplish pink spheres. The structure of AcrB shows ligands bound to the proximal pocket (left) as well as to the deep binding pocket (right). From [59].

Fig. 4

Crystallographic structures of an HME family RND transporter CusA (left, from [14]) and an HAE3 family RND transporter HpnN which crystallizes as a dimer (right, from [25]).

Fig. 5

A. Phylogenic relationship between MmpL transporters in M. tuberculosis. These transporters are divided into two clusters. B. Schematic folding pattern of MmpL exporters, where D1 and D2 denote periplasmic domains and D3 a cytosolic domain. From Chim et al. [43].

Fig. 6

Main routes of intracellular cholesterol movement. Cholesterol esters, a major component of low density lipoprotein (LDL) arrives at the surface of cells of various tissues and are internalized by the process of receptor-mediated endocytosis. Within the endosome, the cholesterol esters are split to generate free cholesterol, which becomes exported out of the late endosomes by NPC1 (in a process involving the participation of soluble cholesterol-binding protein, NPC2) to organelles such as ER and Golgi. Excess cholesterol can also be esterified again by ACAT (acyl-coenzyme A: cholesterol acyltransferase) and stored in intracellular lipid droplets. From [61].

Fig. 7

Comparison of the NPC1 structure (below) with that of HAE1 family RND transporters (above). In the NPC1 structure, the three major extramembrane domains, the N-terminal domain (NTD), the middle luminal domain (MLD) and the C-terminal domain (CTD) are indicated, as well as the sterol-sensing domain (SSD) composed of five transmembrane helices. From Ioannou [61].

Fig. 8

Structure of the NPC1 protein revealed by Cryo-EM. The three extramembrane domains NTD, MLD and CTD of Fig. 7 are here called Domains A, I and C. The transmembrane helices corresponding to the sterol-sensing domain (SSD) are colored in yellow. From [48].