The RND permease superfamily: an ancient, ubiquitous and diverse family that includes human disease and development proteins.
A previous report identified and classified a small family of gram-negative bacterial drug and heavy metal efflux permeases, now commonly referred to as the RND family (TC no. 2.6). We here show that this family is actually a ubiquitous superfamily with representation in all major kingdoms. We report phylogenetic analyses that define seven families within the RND superfamily as follows: (1) the heavy metal efflux (HME) family (gram negative bacteria), (2) the hydrophobe/amphiphile efflux-1 (HAE1) family (gram negative bacteria), (3) the nodulation factor exporter (NFE) family (gram negative bacteria), (4) the SecDF protein-secretion accessory protein (SecDF) family (gram negative and gram positive bacteria as well as archaea), (5) the hydrophobe/amphiphile efflux-2 (HAE2) family (gram positive bacteria), (6) the eukaryotic sterol homeostasis (ESH) family, and (7) the hydrophobe/amphiphile efflux-3 (HAE3) family (archaea and spirochetes). Functionally uncharacterized proteins were identified that are members of the RND superfamily but fall outside of these seven families. Some of the eukaryotic homologues function as enzymes and receptors instead of (or in addition to) transporters. The sizes and topological patterns exhibited by members of all seven families are shown to be strikingly similar, and statistical analyses establish common descent. Multiple alignments of proteins within each family allow derivation of family-specific signature sequences. Structural, functional, mechanistic and evolutionary implication of the reported results are discussed.
Tseng
T T
TT
Department of Biology, University of California at San Diego, La Jolla 92093-0116, USA.
Gratwick
K S
KS
Kollman
J
J
Park
D
D
Nies
D H
DH
Goffeau
A
A
Saier
M H
MH
D000595:Amino Acid Sequence; D000818:Animals; D001105:Archaea / Q000201:enzymology; D001426:Bacterial Proteins / Q000145:classification / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins / Q000145:classification; D005057:Eukaryotic Cells; D006090:Gram-Negative Bacteria / Q000201:enzymology; D006094:Gram-Positive Bacteria / Q000201:enzymology; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000145:classification / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000145:classification / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000145:classification / Q000378:metabolism*; D008969:Molecular Sequence Data; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000201:enzymology*; D009687:Nuclear Proteins / Q000145:classification; D011506:Proteins / Q000145:classification / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors
D001426:Bacterial Proteins; D022762:CCAAT-Enhancer-Binding Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D009687:Nuclear Proteins; D011506:Proteins; C497387:SREBF1 protein, human; C102196:SREBP cleavage-activating protein; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; C075767:secD protein, Bacteria; C075768:secF protein, Bacteria; D006903:Hydroxymethylglutaryl CoA Reductases