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      Deorphanizing the human transmembrane genome: A landscape of uncharacterized membrane proteins

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          Abstract

          The sequencing of the human genome has fueled the last decade of work to functionally characterize genome content. An important subset of genes encodes membrane proteins, which are the targets of many drugs. They reside in lipid bilayers, restricting their endogenous activity to a relatively specialized biochemical environment. Without a reference phenotype, the application of systematic screens to profile candidate membrane proteins is not immediately possible. Bioinformatics has begun to show its effectiveness in focusing the functional characterization of orphan proteins of a particular functional class, such as channels or receptors. Here we discuss integration of experimental and bioinformatics approaches for characterizing the orphan membrane proteome. By analyzing the human genome, a landscape reference for the human transmembrane genome is provided.

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          Gene Ontology: tool for the unification of biology

          Michael Ashburner, Catherine A. Ball, Judith Blake … (2002)
          Genomic sequencing has made it clear that a large fraction of the genes specifying the core biological functions are shared by all eukaryotes. Knowledge of the biological role of such shared proteins in one organism can often be transferred to other organisms. The goal of the Gene Ontology Consortium is to produce a dynamic, controlled vocabulary that can be applied to all eukaryotes even as knowledge of gene and protein roles in cells is accumulating and changing. To this end, three independent ontologies accessible on the World-Wide Web (http://www.geneontology.org) are being constructed: biological process, molecular function and cellular component.
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            TMEM16A confers receptor-activated calcium-dependent chloride conductance.

            Young Duk Yang, Hawon Cho, Jae Koo … (2008)
            Calcium (Ca(2+))-activated chloride channels are fundamental mediators in numerous physiological processes including transepithelial secretion, cardiac and neuronal excitation, sensory transduction, smooth muscle contraction and fertilization. Despite their physiological importance, their molecular identity has remained largely unknown. Here we show that transmembrane protein 16A (TMEM16A, which we also call anoctamin 1 (ANO1)) is a bona fide Ca(2+)-activated chloride channel that is activated by intracellular Ca(2+) and Ca(2+)-mobilizing stimuli. With eight putative transmembrane domains and no apparent similarity to previously characterized channels, ANO1 defines a new family of ionic channels. The biophysical properties as well as the pharmacological profile of ANO1 are in full agreement with native Ca(2+)-activated chloride currents. ANO1 is expressed in various secretory epithelia, the retina and sensory neurons. Furthermore, knockdown of mouse Ano1 markedly reduced native Ca(2+)-activated chloride currents as well as saliva production in mice. We conclude that ANO1 is a candidate Ca(2+)-activated chloride channel that mediates receptor-activated chloride currents in diverse physiological processes.
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              TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity.

              Antonella Caputo, Emanuela Caci, Loretta Ferrera … (2008)
              Calcium-dependent chloride channels are required for normal electrolyte and fluid secretion, olfactory perception, and neuronal and smooth muscle excitability. The molecular identity of these membrane proteins is still unclear. Treatment of bronchial epithelial cells with interleukin-4 (IL-4) causes increased calcium-dependent chloride channel activity, presumably by regulating expression of the corresponding genes. We performed a global gene expression analysis to identify membrane proteins that are regulated by IL-4. Transfection of epithelial cells with specific small interfering RNA against each of these proteins shows that TMEM16A, a member of a family of putative plasma membrane proteins with unknown function, is associated with calcium-dependent chloride current, as measured with halide-sensitive fluorescent proteins, short-circuit current, and patch-clamp techniques. Our results indicate that TMEM16A is an intrinsic constituent of the calcium-dependent chloride channel. Identification of a previously unknown family of membrane proteins associated with chloride channel function will improve our understanding of chloride transport physiopathology and allow for the development of pharmacological tools useful for basic research and drug development.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Acta Pharmacol Sin
                Journal ID (iso-abbrev): Acta Pharmacol. Sin
                Title: Acta Pharmacologica Sinica
                Publisher: Nature Publishing Group
                ISSN (Print): 1671-4083
                ISSN (Electronic): 1745-7254
                Publication date (Print): January 2014
                Publication date (Electronic): 18 November 2013
                Volume: 35
                Issue: 1
                Pages: 11-23
                Affiliations
                [1 ]The Solomon H Snyder Department of Neuroscience, High Throughput Biology Center and Johns Hopkins Ion Channel Center (JHICC), School of Medicine, Johns Hopkins University , Baltimore, MD 21205, USA
                Author notes
                Article
                Publisher Item ID: aps2013142
                DOI: 10.1038/aps.2013.142
                PMC ID: 3880479
                PubMed ID: 24241348
                SO-VID: 71462b60-2d8c-4dce-9779-bf42aab0e427
                Copyright © Copyright © 2014 CPS and SIMM
                License:

                This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                Date received : 28 July 2013
                Date accepted : 08 September 2013
                Categories
                Subject: Review

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: ion channel,bioinformatics,human genome,membrane protein,orphan protein,receptor,transporter,enzyme,drug target
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: ion channel, bioinformatics, human genome, membrane protein, orphan protein, receptor, transporter, enzyme, drug target

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