Functional states of homooligomers: insights from the evolution of glycosyltransferases.
Glycosylation is an important aspect of epigenetic regulation. Glycosyltransferase is a key enzyme in the biosynthesis of glycans, which glycosylates more than half of all proteins in eukaryotes and is involved in a wide range of biological processes. It has been suggested previously that homooligomerization in glycosyltransferases and other proteins might be crucial for their function. In this study, we explore functional homooligomeric states of glycosyltransferases in various organisms, trace their evolution, and perform comparative analyses to find structural features that can mediate or disrupt the formation of different homooligomers. First, we make a structure-based classification of the diverse superfamily of glycosyltransferases and confirm that the majority of the structures are indeed clustered into the GT-A or GT-B folds. We find that homooligomeric glycosyltransferases appear to be as ancient as monomeric glycosyltransferases and go back in evolution to the last universal common ancestor (LUCA). Moreover, we show that interface residues have significant bias to be gapped out or unaligned in the monomers, implying that they might represent features crucial for oligomer formation. Structural analysis of these features reveals that the majority of them represent loops, terminal regions, and helices, indicating that these secondary-structure elements mediate the formation of glycosyltransferases' homooligomers and directly contribute to the specific binding. We also observe relatively short protein regions that disrupt the homodimer interactions, although such cases are rare. These results suggest that relatively small structural changes in the nonconserved regions may contribute to the formation of different functional oligomeric states and might be important in regulation of enzyme activity through homooligomerization.
Hashimoto
Kosuke
K
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, 8600 Rockville Pike, Building 38A 8S814, Bethesda, MD 20894, USA.
Madej
Thomas
T
Bryant
Stephen H
SH
Panchenko
Anna R
AR
D000595:Amino Acid Sequence; D030562:Databases, Protein; D019143:Evolution, Molecular; D016695:Glycosyltransferases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D010802:Phylogeny; D016415:Sequence Alignment
D016695:Glycosyltransferases
Arch Biochem Biophys. 1999 Mar 1;363(1):163-70
10049511
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2358-62
16461900
J Biol Chem. 2008 Jun 13;283(24):16801-7
18400750
Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):668-73
10639137
Carbohydr Res. 2009 May 12;344(7):881-7
19327755
J Mol Biol. 2007 Sep 21;372(3):774-97
17681537
Protein Sci. 2006 Feb;15(2):352-61
16385001
Glycobiology. 2006 Feb;16(2):29R-37R
16037492
Mol Cell. 2000 Jul;6(1):139-48
10949035
Glycobiology. 2006 May;16(5):63R-70R
16014746
Glycobiology. 2009 May;19(5):472-8
19129246
Annu Rev Biophys Biomol Struct. 2000;29:105-53
10940245
J Mol Biol. 2005 Mar 4;346(4):1173-88
15701525
J Biol Chem. 2001 Aug 3;276(31):28641-9
11356854
BMC Struct Biol. 2007 Apr 10;7:23
17425794
Proteins. 2004 Nov 15;57(3):539-47
15382231
Chem Biol. 2002 Dec;9(12):1287-96
12498881
BMC Evol Biol. 2007 Feb 13;7:19
17298668
Biochim Biophys Acta. 1991 Dec 3;1133(1):55-62
1751552
Nat Struct Mol Biol. 2005 Jul;12(7):608-14
15951819
Annu Rev Genomics Hum Genet. 2007;8:261-78
17506657
J Biol Chem. 2008 Oct 10;283(41):27881-27890
18667419
Nucleic Acids Res. 2010 Jan;38(Database issue):D518-24
19843613
Arch Biochem Biophys. 2008 Mar 1;471(1):11-9
18164678
J Mol Biol. 2010 Jan 29;395(4):860-70
19879880
Glycoconj J. 2004;21(1-2):17-24
15467393
J Biol Chem. 2000 Dec 29;275(52):41476-86
11018043
Adv Exp Med Biol. 2008;640:121-63
19065790
Mol Biol Evol. 1987 Jul;4(4):406-25
3447015
Nucleic Acids Res. 2009 Jan;37(Database issue):D233-8
18838391
Curr Opin Chem Biol. 2004 Dec;8(6):617-25
15556405
Nucleic Acids Res. 2009 Jan;37(Database issue):D205-10
18984618
Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13292-7
18757736
Protein Sci. 1995 Dec;4(12):2455-68
8580836
Curr Opin Struct Biol. 2003 Feb;13(1):110-4
12581667
Nat Immunol. 2008 Jun;9(6):593-601
18490910
Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17705-10
19815500
J Biol Chem. 2003 Sep 19;278(38):36323-7
12865427
Annu Rev Biochem. 2008;77:521-55
18518825
Annu Rev Biochem. 2003;72:643-91
12676797
Semin Cancer Biol. 2005 Aug;15(4):300-8
15908230
J Proteome Res. 2009 Feb;8(2):425-6
19133724
Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):2754-9
11880627
Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1321-3
11171945
Protein Eng. 2001 Jun;14(6):403-7
11477219
Nucleic Acids Res. 2007 Jan;35(Database issue):D298-300
17135201
Curr Opin Struct Biol. 1996 Jun;6(3):377-85
8804824
Nat Rev Immunol. 2007 Apr;7(4):255-66
17380156
J Biol Chem. 2008 Apr 4;283(14):8913-8
18198182
Protein Sci. 2009 Oct;18(10):2060-6
19670211
J Biochem. 2008 Jul;144(1):7-14
18367479