title: The extracellular leucine-rich repeat superfamily; a comparative survey and analysis of evolutionary relationships and expression patterns.
abstract: BACKGROUND
  Leucine-rich repeats (LRRs) are highly versatile and evolvable protein-ligand interaction motifs found in a large number of proteins with diverse functions, including innate immunity and nervous system development. Here we catalogue all of the extracellular LRR (eLRR) proteins in worms, flies, mice and humans. We use convergent evidence from several transmembrane-prediction and motif-detection programs, including a customised algorithm, LRRscan, to identify eLRR proteins, and a hierarchical clustering method based on TribeMCL to establish their evolutionary relationships.
  
  
  RESULTS
  This yields a total of 369 proteins (29 in worm, 66 in fly, 135 in mouse and 139 in human), many of them of unknown function. We group eLRR proteins into several classes: those with only LRRs, those that cluster with Toll-like receptors (Tlrs), those with immunoglobulin or fibronectin-type 3 (FN3) domains and those with some other domain. These groups show differential patterns of expansion and diversification across species. Our analyses reveal several clusters of novel genes, including two Elfn genes, encoding transmembrane proteins with eLRRs and an FN3 domain, and six genes encoding transmembrane proteins with eLRRs only (the Elron cluster). Many of these are expressed in discrete patterns in the developing mouse brain, notably in the thalamus and cortex. We have also identified a number of novel fly eLRR proteins with discrete expression in the embryonic nervous system.
  
  
  CONCLUSIONS
  This study provides the necessary foundation for a systematic analysis of the functions of this class of genes, which are likely to include prominently innate immunity, inflammation and neural development, especially the specification of neuronal connectivity.
authors.affiliation: Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland. jadolan@tcd.ie
authors.forename: Jackie
authors.initials: J
authors.lastname: Dolan
authors.forename: Karen
authors.initials: K
authors.lastname: Walshe
authors.forename: Samantha
authors.initials: S
authors.lastname: Alsbury
authors.forename: Karsten
authors.initials: K
authors.lastname: Hokamp
authors.forename: Sean
authors.initials: S
authors.lastname: O'Keeffe
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Okafuji
authors.forename: Suzanne F C
authors.initials: SF
authors.lastname: Miller
authors.forename: Guy
authors.initials: G
authors.lastname: Tear
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Mitchell
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001921:Brain / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D030562:Databases, Protein; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006801:Humans; D007930:Leucine / Q000032:analysis*; D008024:Ligands; D051379:Mice; D005810:Multigene Family; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D020543:Proteome / Q000235:genetics; D012313:RNA / Q000235:genetics / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid
chemical_list: D029742:Caenorhabditis elegans Proteins; D029721:Drosophila Proteins; D008024:Ligands; D011506:Proteins; D020543:Proteome; D012313:RNA; D007930:Leucine