title: Protein similarity networks reveal relationships among sequence, structure, and function within the Cupin superfamily.
abstract: The cupin superfamily is extremely diverse and includes catalytically inactive seed storage proteins, sugar-binding metal-independent epimerases, and metal-dependent enzymes possessing dioxygenase, decarboxylase, and other activities. Although numerous proteins of this superfamily have been structurally characterized, the functions of many of them have not been experimentally determined. We report the first use of protein similarity networks (PSNs) to visualize trends of sequence and structure in order to make functional inferences in this remarkably diverse superfamily. PSNs provide a way to visualize relatedness of structure and sequence among a given set of proteins. Structure- and sequence-based clustering of cupin members reflects functional clustering. Networks based only on cupin domains and networks based on the whole proteins provide complementary information. Domain-clustering supports phylogenetic conclusions that the N- and C-terminal domains of bicupin proteins evolved independently. Interestingly, although many functionally similar enzymatic cupin members bind the same active site metal ion, the structure and sequence clustering does not correlate with the identity of the bound metal. It is anticipated that the application of PSNs to this superfamily will inform experimental work and influence the functional annotation of databases.
authors.affiliation: Department of Chemistry and Biochemistry, Kennesaw State University, Kennesaw, Georgia, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Uberto
authors.forename: Ellen W
authors.initials: EW
authors.lastname: Moomaw
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002238:Carbohydrate Epimerases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002262:Carboxy-Lyases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050558:Cysteine Dioxygenase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019143:Evolution, Molecular; D008359:Mannose-6-Phosphate Isomerase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D010088:Oxidoreductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010944:Plants / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D055314:Seed Storage Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D040681:Structural Homology, Protein
chemical_list: D055314:Seed Storage Proteins; D010088:Oxidoreductases; D050558:Cysteine Dioxygenase; C020598:oxalate oxidase; D002262:Carboxy-Lyases; C021915:oxalate decarboxylase; D002238:Carbohydrate Epimerases; D008359:Mannose-6-Phosphate Isomerase
references.citation: J Mol Biol. 2001 Jan 12;305(2):291-305
references.pmid: 11124907
references.citation: Trends Biochem Sci. 2001 Dec;26(12):740-6
references.pmid: 11738598
references.citation: Biochemistry. 2001 May 29;40(21):6379-87
references.pmid: 11371200
references.citation: Biotechnol Genet Eng Rev. 1998;15:1-32
references.pmid: 9573603
references.citation: J Mol Biol. 1995 Apr 7;247(4):536-40
references.pmid: 7723011
references.citation: Bioinformatics. 2011 Feb 1;27(3):431-2
references.pmid: 21149340
references.citation: J Biol Chem. 2012 Jan 2;287(1):21-28
references.pmid: 22069324
references.citation: J Mol Evol. 1998 Feb;46(2):147-54
references.pmid: 9452516
references.citation: Biochemistry. 2003 May 20;42(19):5547-54
references.pmid: 12741810
references.citation: Microbiol Mol Biol Rev. 2000 Mar;64(1):153-79
references.pmid: 10704478
references.citation: J Biol Chem. 2004 May 7;279(19):19867-74
references.pmid: 14871895
references.citation: J Biol Chem. 2007 Jun 29;282(26):19227-36
references.pmid: 17459872
references.citation: Biochemistry. 2005 Jan 11;44(1):193-201
references.pmid: 15628860
references.citation: Biopolymers. 2009 Dec;91(12):1189-95
references.pmid: 19226621
references.citation: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2005 May 1;61(Pt 5):469-72
references.pmid: 16511070
references.citation: J Biol Chem. 1999 Jan 15;274(3):1193-5
references.pmid: 9880484
references.citation: J Biol Chem. 2005 Aug 5;280(31):28675-82
references.pmid: 15951572
references.citation: EMBO Rep. 2005 Apr;6(4):315-20
references.pmid: 15809658
references.citation: Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14568-72
references.pmid: 20679243
references.citation: Biochemistry. 2005 May 31;44(21):7623-31
references.pmid: 15909977
references.citation: J Biol Chem. 2012 Jan 2;287(1):29-34
references.pmid: 22069326
references.citation: FEBS J. 2011 Apr;278(7):1086-97
references.pmid: 21251231
references.citation: Nat Rev Genet. 2006 Sep;7(9):715-27
references.pmid: 16983801
references.citation: Structure. 2007 Sep;15(9):1040-52
references.pmid: 17850744
references.citation: Biochemistry. 2009 Nov 24;48(46):11108-16
references.pmid: 19842715
references.citation: Acta Crystallogr D Biol Crystallogr. 2000 Nov;56(Pt 11):1476-8
references.pmid: 11053858
references.citation: Cell Res. 2010 Feb;20(2):166-73
references.pmid: 20101266
references.citation: Biochim Biophys Acta. 2003 May 30;1648(1-2):99-104
references.pmid: 12758152
references.citation: Nature. 2008 Oct 23;455(7216):1138-42
references.pmid: 18948958
references.citation: J Mol Biol. 1994 May 20;238(5):748-76
references.pmid: 8182747
references.citation: Nature. 2012 Aug 16;488(7411):404-8
references.pmid: 22842901
references.citation: Cell Res. 2010 Aug;20(8):886-98
references.pmid: 20567261
references.citation: J Biol Chem. 2012 Jan 2;287(1):35-42
references.pmid: 22069325
references.citation: FEBS Lett. 1992 Aug 10;308(1):1-3
references.pmid: 1644197
references.citation: Bioinformatics. 2012 Nov 1;28(21):2845-6
references.pmid: 22962345
references.citation: Structure. 2003 Jun;11(6):715-23
references.pmid: 12791259
references.citation: Biochem J. 2011 Jan 15;433(2):295-302
references.pmid: 21067515
references.citation: Acta Crystallogr D Biol Crystallogr. 2002 Jul;58(Pt 7):1226-8
references.pmid: 12077451
references.citation: Nucleic Acids Res. 2002 Jan 1;30(1):264-7
references.pmid: 11752311
references.citation: J Mol Biol. 2007 Jan 5;365(1):146-59
references.pmid: 17046787
references.citation: Nat Struct Biol. 1996 May;3(5):470-9
references.pmid: 8612079
references.citation: FEBS Lett. 2004 Jan 16;557(1-3):45-8
references.pmid: 14741339
references.citation: Genes Dev. 2002 Jun 15;16(12):1466-71
references.pmid: 12080085
references.citation: Proteins. 2006 Apr 1;63(1):261-5
references.pmid: 16411240
references.citation: Curr Opin Chem Biol. 2006 Oct;10(5):492-7
references.pmid: 16935022
references.citation: Cell. 2006 May 19;125(4):691-702
references.pmid: 16677698
references.citation: Annu Rev Biochem. 2001;70:209-46
references.pmid: 11395407
references.citation: Nat Struct Biol. 2000 Nov;7(11):1036-40
references.pmid: 11062559
references.citation: Acta Crystallogr D Biol Crystallogr. 2003 Aug;59(Pt 8):1507-9
references.pmid: 12876368
references.citation: Nucleic Acids Res. 2010 Sep;38(16):5261-79
references.pmid: 20423905
references.citation: Biochim Biophys Acta. 2012 Sep;1823(9):1531-52
references.pmid: 22569643
references.citation: Nat Struct Biol. 2000 May;7(5):398-402
references.pmid: 10802738
references.citation: Proteins. 2006 Aug 15;64(3):808-13
references.pmid: 16783794
references.citation: PLoS Comput Biol. 2009 Oct;5(10):e1000541
references.pmid: 19851441
references.citation: Trends Biochem Sci. 2011 Jan;36(1):7-18
references.pmid: 20728359
references.citation: Acta Crystallogr D Biol Crystallogr. 2004 May;60(Pt 5):895-902
references.pmid: 15103135
references.citation: J Biol Chem. 2010 Nov 5;285(45):34503-7
references.pmid: 20739293
references.citation: Biochemistry. 2006 Jan 24;45(3):1009-16
references.pmid: 16411777
references.citation: Genes Dev. 2011 Nov 1;25(21):2266-77
references.pmid: 22002947
references.citation: PLoS One. 2009;4(2):e4345
references.pmid: 19190775
references.citation: J Biol Chem. 2012 Jan 2;287(1):1-2
references.pmid: 22069328
references.citation: Biochim Biophys Acta. 2010 Jul;1804(7):1432-42
references.pmid: 20215054
references.citation: Biochemistry. 2005 May 31;44(21):7632-43
references.pmid: 15909978
references.citation: J Biol Chem. 2000 Aug 11;275(32):24608-12
references.pmid: 10827167
references.citation: Structure. 2002 Feb;10(2):259-68
references.pmid: 11839311
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D290-301
references.pmid: 22127870
references.citation: Nucleic Acids Res. 2004 Jan 1;32(Database issue):D226-9
references.pmid: 14681400
references.citation: J Bacteriol. 2005 Aug;187(16):5520-7
references.pmid: 16077096
references.citation: J Biol Chem. 2009 Nov 13;284(46):31882-92
references.pmid: 19776011
references.citation: J Biol Chem. 2011 Nov 11;286(45):39318-27
references.pmid: 21917921
references.citation: J Biol Chem. 2001 Nov 23;276(47):43627-34
references.pmid: 11546787
references.citation: J Biol Chem. 2006 Mar 10;281(10):6428-33
references.pmid: 16291738
references.citation: Nat Struct Biol. 2002 Dec;9(12):966-72
references.pmid: 12402029
references.citation: Nucleic Acids Res. 2011 Mar;39(4):1576-85
references.pmid: 20972222
references.citation: Trends Parasitol. 2009 Dec;25(12):573-81
references.pmid: 19854678
references.citation: Nucleic Acids Res. 2005 Apr 22;33(7):2302-9
references.pmid: 15849316
references.citation: Curr Opin Chem Biol. 2003 Feb;7(1):12-20
references.pmid: 12547421
references.citation: J Biomol NMR. 2006 Feb;34(2):117-27
references.pmid: 16518698
references.citation: Biochemistry. 2002 Jun 18;41(24):7659-69
references.pmid: 12056897
references.citation: Phytochemistry. 2004 Jan;65(1):7-17
references.pmid: 14697267
references.citation: J Mol Biol. 2001 Apr 13;307(5):1271-92
references.pmid: 11292341
references.citation: J Mol Biol. 2011 Feb 11;406(1):1-8
references.pmid: 21167174
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3084-9
references.pmid: 16492780
references.citation: J Mol Biol. 2012 Feb 24;416(3):319-27
references.pmid: 22227394
references.citation: Proteins. 2011 Nov;79(11):3082-98
references.pmid: 21948213
references.citation: PLoS One. 2009 May 29;4(5):e5736
references.pmid: 19478949
references.citation: Trends Biochem Sci. 2001 Jan;26(1):7-9
references.pmid: 11165500
references.citation: Acta Crystallogr D Biol Crystallogr. 2009 Jul;65(Pt 7):724-32
references.pmid: 19564693
references.citation: J Biol Chem. 2007 Feb 2;282(5):3391-402
references.pmid: 17135237
references.citation: J Struct Funct Genomics. 2009 Apr;10(2):107-25
references.pmid: 19219566