title: Prototypes of elementary functional loops unravel evolutionary connections between protein functions.
abstract: BACKGROUND
  Earlier studies of protein structure revealed closed loops with a characteristic size 25-30 residues and ring-like shape as a basic universal structural element of globular proteins. Elementary functional loops (EFLs) have specific signatures and provide functional residues important for binding/activation and principal chemical transformation steps of the enzymatic reaction. The goal of this work is to show how these functional loops evolved from pre-domain peptides and to find a set of prototypes from which the EFLs of contemporary proteins originated.
  
  
  RESULTS
  This article describes a computational method for deriving prototypes of EFLs based on the sequences of complete genomes. The procedure comprises the iterative derivation of sequence profiles followed by their hierarchical clustering. The scoring function takes into account information content on profile positions, thus preserving the signature. The statistical significance of scores is evaluated from the empirical distribution of scores of the background model. A set of prototypes of EFLs from archaeal proteomes is derived. This set delineates evolutionary connections between major functions and illuminates how folds and functions emerged in pre-domain evolution as a combination of prototypes.
authors.affiliation: Bergen Center for Computational Science and Department of Informatics, University of Bergen, Bergen, Norway.
authors.forename: Alexander
authors.initials: A
authors.lastname: Goncearenco
authors.forename: Igor N
authors.initials: IN
authors.lastname: Berezovsky
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000595:Amino Acid Sequence; D019843:Archaeal Proteins / Q000737:chemistry* / Q000235:genetics; D001483:Base Sequence; D019295:Computational Biology / Q000379:methods*; D019143:Evolution, Molecular; D020745:Genome, Archaeal; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017510:Protein Folding; D020543:Proteome
chemical_list: D019843:Archaeal Proteins; D020543:Proteome
references.citation: Bioinformatics. 2006 Jul 1;22(13):1658-9
references.pmid: 16731699
references.citation: Nucleic Acids Res. 2007 Jan;35(Database issue):D253-9
references.pmid: 17068077
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5441-6
references.pmid: 18385384
references.citation: EMBO J. 2004 Aug 18;23(16):3196-205
references.pmid: 15272305
references.citation: J Mol Biol. 2002 Aug 30;321(5):741-65
references.pmid: 12206759
references.citation: Protein Eng. 1999 Feb;12(2):85-94
references.pmid: 10195279
references.citation: J Mol Biol. 2001 Apr 13;307(5):1419-26
references.pmid: 11292352
references.citation: Curr Opin Chem Biol. 2006 Oct;10(5):492-7
references.pmid: 16935022
references.citation: Nucleic Acids Res. 2009 Feb;37(3):815-24
references.pmid: 19088134
references.citation: J Biol Chem. 2009 Jun 26;284(26):17796-807
references.pmid: 19244233
references.citation: Nat Genet. 2005 Jan;37(1):73-6
references.pmid: 15568024
references.citation: Protein Sci. 1998 Feb;7(2):233-42
references.pmid: 9521098
references.citation: J Mol Biol. 2001 Nov 2;313(4):903-19
references.pmid: 11697912
references.citation: Nucleic Acids Res. 1997 Sep 1;25(17):3389-402
references.pmid: 9254694
references.citation: Nucleic Acids Res. 2010 Jan;38(Database issue):D161-6
references.pmid: 19858104
references.citation: Trends Biochem Sci. 2005 Nov;30(11):622-9
references.pmid: 16214343
references.citation: Bioinformatics. 2000 Jul;16(7):613-8
references.pmid: 11038331
references.citation: J Struct Biol. 2001 May-Jun;134(2-3):191-203
references.pmid: 11551179
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):254-6
references.pmid: 10592239
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D138-41
references.pmid: 14681378
references.citation: Nature. 1996 Apr 25;380(6576):730-4
references.pmid: 8614471
references.citation: J Mol Biol. 2002 Apr 26;318(2):595-608
references.pmid: 12051862
references.citation: Nature. 1974 Jul 19;250(463):194-9
references.pmid: 4368490
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):257-9
references.pmid: 10592240
references.citation: Science. 2009 Apr 10;324(5924):203-7
references.pmid: 19359577
references.citation: Bioinformatics. 2009 Aug 1;25(15):1862-8
references.pmid: 19470584
references.citation: Nucleic Acids Res. 2007;35(14):4678-85
references.pmid: 17596268
references.citation: J Mol Biol. 2009 Jul 17;390(3):560-77
references.pmid: 19447117
references.citation: Science. 2003 Jun 13;300(5626):1701-3
references.pmid: 12805536
references.citation: Nucleic Acids Res. 2000 Jan 1;28(1):304-5
references.pmid: 10592255
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D205-10
references.pmid: 18984618
references.citation: Protein Eng. 2003 Mar;16(3):161-7
references.pmid: 12702795
references.citation: FEBS Lett. 2000 Jan 28;466(2-3):283-6
references.pmid: 10682844
references.citation: Curr Opin Chem Biol. 2008 Apr;12(2):151-8
references.pmid: 18284924
references.citation: Fold Des. 1998;3(6):497-512
references.pmid: 9889159
references.citation: Nucleic Acids Res. 2009 Jan;37(Database issue):D26-31
references.pmid: 18940867
references.citation: Curr Opin Struct Biol. 2003 Feb;13(1):110-4
references.pmid: 12581667
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11079-84
references.pmid: 19541617
references.citation: Nat Chem Biol. 2009 Aug;5(8):521-5
references.pmid: 19620987
references.citation: Methods Enzymol. 1996;266:554-71
references.pmid: 8743706
references.citation: Nucleic Acids Res. 2003 Jan 15;31(2):683-9
references.pmid: 12527777
references.citation: Adv Protein Chem. 1952;7:1-67
references.pmid: 14933251
references.citation: J Mol Biol. 2007 Oct 5;372(5):1261-77
references.pmid: 17727879