Bioinformatic characterization of the Anoctamin Superfamily of Ca2+-activated ion channels and lipid scramblases

Arturo Medrano-Soto,Milton H Saier,Gabriel Moreno-Hagelsieb,Zachary S Ye,Daniel Mclaughlin,Kevin J Hendargo,Olaf Strauß

doi:10.1371/journal.pone.0192851

Arturo Medrano-Soto, Milton H Saier + Show 5 more

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https://doi.org/10.1371/journal.pone.0192851

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Abstract

Our laboratory has developed bioinformatic strategies for identifying distant phylogenetic relationships and characterizing families and superfamilies of transport proteins. Results using these tools suggest that the Anoctamin Superfamily of cation and anion channels, as well as lipid scramblases, includes three functionally characterized families: the Anoctamin (ANO), Transmembrane Channel (TMC) and Ca2+-permeable Stress-gated Cation Channel (CSC) families; as well as four families of functionally uncharacterized proteins, which we refer to as the Anoctamin-like (ANO-L), Transmembrane Channel-like (TMC-L), and CSC-like (CSC-L1 and CSC-L2) families. We have constructed protein clusters and trees showing the relative relationships among the seven families. Topological analyses suggest that the members of these families have essentially the same topologies. Comparative examination of these homologous families provides insight into possible mechanisms of action, indicates the currently recognized organismal distributions of these proteins, and suggests drug design potential for the disease-related channel proteins.

Highlights

In January of 1993, our laboratory reported bioinformatic studies that provided the first evidence suggesting an evolutionary relationship among drug resistance exporters, glucose facilitators, metabolite uptake proteins, sugar phosphate antiporters, and the well-studied lactose permease of Escherichia coli [1]
As a result of the analyses reported below, within 1.A.17, the Anoctamin (ANO) family is represented by the identifier 1.A.17.1, Transmembrane Channel (TMC) is represented by 1.A.17.4, and CSC is represented by 1.A.17.5
The four families consisting of proteins of unknown function were given the identifiers 1.A.17.2, 1.A.17.6, 1.A.17.3, and 1.A.17.7

Summary

Introduction

In January of 1993, our laboratory reported bioinformatic studies that provided the first evidence suggesting an evolutionary relationship among drug resistance exporters, glucose facilitators, metabolite uptake proteins, sugar phosphate antiporters, and the well-studied lactose permease of Escherichia coli [1] We named this superfamily the Major Facilitator Superfamily (MFS). In 2016, there were nearly 100 families in the MFS, and our most recent unpublished efforts have identified additional MFS family members. It appears that transmembrane peptidases and glycosyltransferases may be members of this superfamily Proposals for the pathways of its evolution have been presented [6,7,8], and comparison of high resolution x-ray structures support these proposals [9,10,11,12]

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