title: LRRC8 proteins share a common ancestor with pannexins, and may form hexameric channels involved in cell-cell communication.
abstract: Leucine-rich repeat-containing 8 (LRRC8) proteins are composed of four transmembrane helices and 17 leucine-rich repeats (LRR). Although LRRC8 proteins have been associated with important processes, like maturation of B cells or adipocyte differentiation, their biology and molecular function are largely unknown. We found that LRRC8 proteins originated from the combination of a pannexin and an LRR domain (most likely related to the SHOC2, LAP, RSU1 and LRRIQ4 protein families) before the diversification of chordates. We propose that, like pannexins, LRRC8 proteins form hexameric channels, which participate in cell-cell communication processes. According to the inferred topological model, and contrary to what was previously assumed, the six LRR domains are located in the cytoplasm, and could participate in the organisation of signalling cascades. By compiling available proteomics and gene expression data, and on the basis of the LRRC8 proposed hexameric channel structure, we present clues to the function of this family.
authors.affiliation: Departamento de Biodiversidad y Biología Evolutiva, Museo Nacional de Ciencias Naturales CSIC, José Gutiérrez Abascal, Madrid, Spain. abascal@mncn.csic.es
authors.forename: Federico
authors.initials: F
authors.lastname: Abascal
authors.forename: Rafael
authors.initials: R
authors.lastname: Zardoya
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002450:Cell Communication; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D017630:Connexins / Q000145:classification / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D007930:Leucine / Q000378:metabolism; D008565:Membrane Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D010802:Phylogeny; D025941:Protein Interaction Mapping; D020836:Protein Structure, Quaternary; D021381:Protein Transport; D013329:Structure-Activity Relationship
chemical_list: D017630:Connexins; D007473:Ion Channels; C485976:LRRC8A protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D007930:Leucine; D002118:Calcium