title: Architecture and metamorphosis.
abstract: When compared to other conserved housekeeping protein families, such as ribosomal proteins, during the evolution of higher eukaryotes, aminoacyl-tRNA synthetases (aaRSs) show an apparent high propensity to add new sequences, and especially new domains. The stepwise emergence of those new domains is consistent with their involvement in a broad range of biological functions beyond protein synthesis, and correlates with the increasing biological complexity of higher organisms. These new domains have been extensively characterized based on their evolutionary origins and their sequence, structural, and functional features. While some of the domains are uniquely found in aaRSs and may have originated from nucleic acid binding motifs, others are common domain modules mediating protein-protein interactions that play a critical role in the assembly of the multi-synthetase complex (MSC). Interestingly, the MSC has emerged from a miniature complex in yeast to a large stable complex in humans. The human MSC consists of nine aaRSs (LysRS, ArgRS, GlnRS, AspRS, MetRS, IleRS, LeuRS, GluProRS, and bifunctional aaRs) and three scaffold proteins (AIMP1/p43, AIMP2/p38, and AIMP3/p18), and has a molecular weight of 1.5 million Dalton. The MSC has been proposed to have a functional dualism: facilitating protein synthesis and serving as a reservoir of non-canonical functions associated with its synthetase and non-synthetase components. Importantly, domain additions and functional expansions are not limited to the components of the MSC and are found in almost all aaRS proteins. From a structural perspective, multi-functionalities are represented by multiple conformational states. In fact, alternative conformations of aaRSs have been generated by various mechanisms from proteolysis to alternative splicing and posttranslational modifications, as well as by disease-causing mutations. Therefore, the metamorphosis between different conformational states is connected to the activation and regulation of the novel functions of aaRSs in higher eukaryotes.
authors.affiliation: Department of Cancer Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL, 33410, USA, GuoMin@scripps.edu.
authors.forename: Min
authors.initials: M
authors.lastname: Guo
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D056890:Eukaryota / Q000201:enzymology / Q000235:genetics; D019143:Evolution, Molecular; D006801:Humans; D011487:Protein Conformation; D013045:Species Specificity
chemical_list: D000604:Amino Acyl-tRNA Synthetases
references.citation: J Mol Biol. 2008 Sep 5;381(3):763-71
references.pmid: 18598703
references.citation: Biochem Biophys Res Commun. 2001 Nov 2;288(3):509-14
references.pmid: 11676472
references.citation: EMBO Rep. 2008 Mar;9(3):280-6
references.pmid: 18274552
references.citation: Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10128-33
references.pmid: 8816763
references.citation: Genome Res. 2003 Mar;13(3):407-12
references.pmid: 12618371
references.citation: J Cell Sci. 2004 Aug 1;117(Pt 17):3725-34
references.pmid: 15286174
references.citation: Mol Biol Evol. 2011 Jan;28(1):437-47
references.pmid: 20829344
references.citation: Structure. 2007 Jul;15(7):793-805
references.pmid: 17637340
references.citation: Genes Dev. 2005 Mar 1;19(5):583-92
references.pmid: 15706032
references.citation: Biochemistry. 2005 Feb 1;44(4):1344-52
references.pmid: 15667228
references.citation: Science. 1999 Apr 2;284(5411):147-51
references.pmid: 10102815
references.citation: J Biochem. 1996 Jun;119(6):1182-8
references.pmid: 8827456
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11782-7
references.pmid: 19561293
references.citation: Int J Biochem Cell Biol. 2003 Nov;35(11):1548-57
references.pmid: 12824064
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11206-11
references.pmid: 18695251
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14903-7
references.pmid: 14630953
references.citation: Nucleic Acids Res. 2012 Nov 1;40(20):10494-506
references.pmid: 22941646
references.citation: Cell. 2012 Apr 13;149(2):410-24
references.pmid: 22424946
references.citation: J Mol Biol. 1999 Jan 8;285(1):183-95
references.pmid: 9878398
references.citation: Mol Cell. 2008 Feb 29;29(4):419-27
references.pmid: 18313381
references.citation: Curr Neurol Neurosci Rep. 2011 Feb;11(1):78-88
references.pmid: 21080241
references.citation: Nature. 2009 Sep 3;461(7260):60-5
references.pmid: 19680239
references.citation: EMBO J. 2000 Dec 15;19(24):6908-17
references.pmid: 11118226
references.citation: J Biol Chem. 2002 Jan 18;277(3):1762-9
references.pmid: 11706011
references.citation: FEBS Lett. 2010 Sep 24;584(18):3842-9
references.pmid: 20728442
references.citation: J Biol Chem. 2011 Aug 12;286(32):28476-87
references.pmid: 21685384
references.citation: J Biol Chem. 2006 Dec 15;281(50):38663-7
references.pmid: 17062567
references.citation: Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):178-83
references.pmid: 11773625
references.citation: J Biol Chem. 2001 Feb 23;276(8):6030-6
references.pmid: 11096076
references.citation: Nat Chem Biol. 2012 Apr 15;8(6):547-54
references.pmid: 22504299
references.citation: EMBO J. 1996 Oct 1;15(19):5437-48
references.pmid: 8895587
references.citation: Nat Commun. 2012 Feb 21;3:681
references.pmid: 22353712
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2331-6
references.pmid: 18272479
references.citation: Electrophoresis. 1999 Apr-May;20(4-5):984-93
references.pmid: 10344276
references.citation: Protein Sci. 2010 Dec;19(12):2475-84
references.pmid: 20954242
references.citation: Structure. 2010 Mar 10;18(3):343-53
references.pmid: 20223217
references.citation: FASEB J. 2012 Oct;26(10):4142-59
references.pmid: 22751010
references.citation: Structure. 2012 Sep 5;20(9):1470-7
references.pmid: 22958643
references.citation: J Mol Evol. 2002 Dec;55(6):727-33
references.pmid: 12486531
references.citation: Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15369-74
references.pmid: 12427973
references.citation: Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7435-9
references.pmid: 8052601
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):7912-6
references.pmid: 12060739
references.citation: Cell. 1997 Apr 18;89(2):263-73
references.pmid: 9108481
references.citation: EMBO J. 2001 Feb 1;20(3):570-8
references.pmid: 11157763
references.citation: J Proteome Res. 2008 Mar;7(3):1274-87
references.pmid: 18247557
references.citation: Nat Struct Biol. 2001 Apr;8(4):344-8
references.pmid: 11276256
references.citation: Nat Rev Mol Cell Biol. 2010 Sep;11(9):668-74
references.pmid: 20700144
references.citation: Mol Cell. 2012 Apr 13;46(1):105-10
references.pmid: 22424774
references.citation: Mol Cell. 2009 Jun 12;34(5):603-11
references.pmid: 19524539
references.citation: Mol Cell. 2012 Apr 13;46(1):4-6
references.pmid: 22500735
references.citation: Science. 2009 Aug 14;325(5942):834-40
references.pmid: 19608861
references.citation: Mol Cell. 2013 Jan 10;49(1):30-42
references.pmid: 23159739
references.citation: Trends Biochem Sci. 2007 Apr;32(4):158-64
references.pmid: 17321138
references.citation: J Virol. 2004 Feb;78(3):1595-601
references.pmid: 14722314
references.citation: Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4488-93
references.pmid: 10200289
references.citation: FEBS Lett. 2010 Jan 21;584(2):434-42
references.pmid: 19932696
references.citation: Nucleic Acids Res. 2012 Apr;40(8):3723-31
references.pmid: 22180531
references.citation: Cell. 2004 Oct 15;119(2):195-208
references.pmid: 15479637
references.citation: FEBS Lett. 2003 May 8;542(1-3):119-24
references.pmid: 12729910
references.citation: J Mol Biol. 2011 Jan 28;405(4):1056-69
references.pmid: 21134380
references.citation: RNA Biol. 2009 Jan-Mar;6(1):31-4
references.pmid: 19106621
references.citation: EMBO J. 2000 Feb 1;19(3):445-52
references.pmid: 10654942
references.citation: J Biol Chem. 2008 May 16;283(20):14032-40
references.pmid: 18343821
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):19635-40
references.pmid: 22106287
references.citation: Biochemistry. 2011 Aug 23;50(33):7132-45
references.pmid: 21732632
references.citation: Nucleic Acids Res. 2008 Nov;36(20):6386-95
references.pmid: 18838389
references.citation: Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):173-7
references.pmid: 11773626
references.citation: Biochim Biophys Acta. 1994 Apr 21;1199(3):293-7
references.pmid: 8161568
references.citation: J Biol Chem. 2011 Apr 1;286(13):11563-8
references.pmid: 21310955
references.citation: J Biol Chem. 1993 Mar 15;268(8):6014-23
references.pmid: 8449960
references.citation: Mol Cell Proteomics. 2006 May;5(5):858-67
references.pmid: 16474175
references.citation: Biomol NMR Assign. 2013 Oct;7(2):289-92
references.pmid: 23065336
references.citation: FEBS Lett. 2010 Jan 21;584(2):427-33
references.pmid: 19914242
references.citation: Prog Nucleic Acid Res Mol Biol. 1991;40:95-142
references.pmid: 2031086
references.citation: FEBS Lett. 2012 Jul 30;586(16):2232-8
references.pmid: 22683511
references.citation: J Biol Chem. 1982 Jun 10;257(11):6003-6
references.pmid: 7076660
references.citation: J Biol Chem. 2009 Mar 6;284(10):6053-60
references.pmid: 19131329
references.citation: Biochemistry. 2006 Jan 31;45(4):1338-44
references.pmid: 16430231
references.citation: J Biol Chem. 1994 Jan 21;269(3):2086-92
references.pmid: 8294461
references.citation: J Biol Chem. 1995 Jan 6;270(1):397-403
references.pmid: 7814400
references.citation: EMBO J. 1999 Jun 15;18(12):3475-83
references.pmid: 10369686
references.citation: J Biol Chem. 1985 Aug 15;260(17):9843-7
references.pmid: 4019497
references.citation: J Biol Chem. 1998 May 1;273(18):11267-73
references.pmid: 9556618
references.citation: IUBMB Life. 2010 Apr;62(4):296-302
references.pmid: 20306515
references.citation: Nucleic Acids Res. 2004 Feb 02;32(2):719-27
references.pmid: 14757836
references.citation: Proc Natl Acad Sci U S A. 2011 Jul 26;108(30):12307-12
references.pmid: 21737751
references.citation: J Mol Biol. 2001 Jan 19;305(3):451-8
references.pmid: 11152603
references.citation: FEBS Lett. 2010 Jan 21;584(2):359-65
references.pmid: 19914238
references.citation: J Biol Chem. 2006 Jul 14;281(28):19449-56
references.pmid: 16702215
references.citation: Chem Biol. 2009 May 29;16(5):531-9
references.pmid: 19477417
references.citation: Nature. 1998 Sep 24;395(6700):347-53
references.pmid: 9759724
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):9976-81
references.pmid: 17545306
references.citation: J Biol Chem. 1999 Feb 19;274(8):4545-50
references.pmid: 9988688
references.citation: Nucleic Acids Res. 2006;34(14):3968-79
references.pmid: 16914447
references.citation: J Biol Chem. 2005 Nov 18;280(46):38870-8
references.pmid: 16169847
references.citation: Biochim Biophys Acta. 2009 Feb;1794(2):347-54
references.pmid: 19064003
references.citation: Proc Natl Acad Sci U S A. 2011 May 17;108(20):8239-44
references.pmid: 21536907
references.citation: Aging Cell. 2010 Oct;9(5):810-22
references.pmid: 20726853
references.citation: J Biol Chem. 1989 Oct 5;264(28):16608-12
references.pmid: 2674137
references.citation: J Cell Sci. 2009 Aug 1;122(Pt 15):2710-5
references.pmid: 19584093
references.citation: Biochem Biophys Res Commun. 2003 Apr 18;303(4):985-93
references.pmid: 12684031
references.citation: Circ Res. 2009 Jun 5;104(11):1260-6
references.pmid: 19423847
references.citation: FEBS J. 2005 May;272(9):2118-31
references.pmid: 15853797
references.citation: EMBO J. 2000 May 15;19(10):2371-80
references.pmid: 10811628
references.citation: Nat Struct Mol Biol. 2010 Jan;17(1):57-61
references.pmid: 20010843
references.citation: Am J Hum Genet. 2010 Oct 8;87(4):560-6
references.pmid: 20920668
references.citation: Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8485-9
references.pmid: 8710896
references.citation: J Phys Chem B. 2010 Dec 16;114(49):16273-9
references.pmid: 21058683
references.citation: Mol Cell. 2009 Jul 31;35(2):164-80
references.pmid: 19647514
references.citation: Chem Biol. 2007 Dec;14(12):1323-33
references.pmid: 18096501
references.citation: J Biol Chem. 2003 Jan 17;278(3):1472-9
references.pmid: 12417586
references.citation: Clin Genet. 1974;6(2):98-118
references.pmid: 4430158
references.citation: Nature. 2004 Oct 21;431(7011):931-45
references.pmid: 15496913
references.citation: Nat Genet. 2006 Feb;38(2):197-202
references.pmid: 16429158
references.citation: PLoS Genet. 2011 Dec;7(12):e1002399
references.pmid: 22144914
references.citation: Trends Biochem Sci. 2005 Oct;30(10):569-74
references.pmid: 16125937
references.citation: Mol Cell. 2007 Jan 12;25(1):113-26
references.pmid: 17218275
references.citation: J Biol Chem. 1992 Sep 5;267(25):17701-9
references.pmid: 1517216
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11239-44
references.pmid: 17595294
references.citation: J Mol Biol. 2000 Dec 15;304(5):983-94
references.pmid: 11124041
references.citation: Protein Sci. 2000 Feb;9(2):218-31
references.pmid: 10716174
references.citation: J Biol Chem. 1999 Aug 13;274(33):23155-9
references.pmid: 10438485
references.citation: J Biol Chem. 1987 Mar 25;262(9):3982-7
references.pmid: 3644822
references.citation: Circ Res. 2009 Jun 5;104(11):1253-9
references.pmid: 19423848
references.citation: Am J Hum Genet. 2003 May;72(5):1293-9
references.pmid: 12690580
references.citation: Biochemistry. 2005 Mar 22;44(11):4216-21
references.pmid: 15766249
references.citation: EMBO J. 2001 Dec 3;20(23):6889-98
references.pmid: 11726524
references.citation: Protein Sci. 1994 Nov;3(11):2045-54
references.pmid: 7703850
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16209-14
references.pmid: 19805282
references.citation: Protein Sci. 1998 Jan;7(1):79-87
references.pmid: 9514262
references.citation: Nucleic Acids Res. 2000 Aug 1;28(15):2866-72
references.pmid: 10908348
references.citation: EMBO J. 2011 Mar 2;30(5):846-58
references.pmid: 21285945
references.citation: Mol Cell. 2008 Mar 28;29(6):679-90
references.pmid: 18374644
references.citation: J Biol Chem. 2012 Jun 8;287(24):20504-8
references.pmid: 22549774
references.citation: FEBS Lett. 2008 Jun 25;582(15):2178-82
references.pmid: 18538672