EPL和PTS在生物合成主链环肽方面的应用研究进展
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摘要
内含肽作为宿主蛋白的组成成分,不仅可将自身从宿主蛋白中剪切,而且还可催化外显肽的连接。内含肽广泛分布于生物界的三大领域及病毒蛋白中。蛋白质剪接是由内含肽介导的一种翻译后自催化加工过程,整个过程不需要酶或辅因子的参与。蛋白质剪接包括四步分子内的反应及内含肽和外显肽中部分发挥关键催化功能的氨基酸残基。表达蛋白质连接(EPL)和蛋白质反式剪接(PTS)技术是借助内含肽及蛋白质剪接发展起来的。该文主要就这两项技术在生物合成主链环肽文库方面的应用领域及未来的应用前景进行了综述。
As internal protein elements,inteins are self-excised from their host protein and catalyze ligation of exteins with a peptide bond. They are widely found in all the three domains of the biological kingdom,and in viral proteins. Inteinmediated protein splicing is a posttranslational autocatalytic process that does not require auxiliary enzymes or cofactors.Protein splicing involves four intramolecular reactions and a small number of key catalytic residues in the intein and exteins.The development of expressed protein ligation( EPL) and protein trans-splicing( PTS) is assisted by inteins and protein splicing. This review introduces the biosynthesis of backbone-cyclized peptides libraries,and describes the applications of cyclic polypeptides and their prospective applications in the future.
As internal protein elements,inteins are self-excised from their host protein and catalyze ligation of exteins with a peptide bond. They are widely found in all the three domains of the biological kingdom,and in viral proteins. Inteinmediated protein splicing is a posttranslational autocatalytic process that does not require auxiliary enzymes or cofactors.Protein splicing involves four intramolecular reactions and a small number of key catalytic residues in the intein and exteins.The development of expressed protein ligation( EPL) and protein trans-splicing( PTS) is assisted by inteins and protein splicing. This review introduces the biosynthesis of backbone-cyclized peptides libraries,and describes the applications of cyclic polypeptides and their prospective applications in the future.
引文
[1]Kane PM,Yamashiro CT,Wolczyk DF,et al.Protein splicing converts the yeast TFP1 gene product to the 69-k D subunit of the vacuolar H(+)-adenosine triphosphatase[J].Science,1990,250(4981):651-657.
[2]Hirata R,Ohsumk Y,Nakano A,et al.Molecular structure of a gene,VMA1,encoding the catalytic subunit of H(+)-translocating adenosine triphosphatase from vacuolar membranes of Saccharomyces cerevisiae[J].J Biol Chem,1990,265(12):6726-6733.
[3]Perler FB,Davis EO,Dean GE,et al.Protein splicing elements:inteins and exteins,a definition of terms,and recommended nomenclature[J].Nucleic Acids Res,1994,22(7):1125-1127.
[4]Muir TW,Sondhi D,Cole PA.Expressed protein ligation:a general method for protein engineering[J].Proc Natl Acad Sci USA,1998,95(12):6705-6710.
[5]Evans TC Jr,Benner J,Xu MQ.Semisynthesis of cytotoxic proteins using a modified protein splicing element[J].Protein Sci,1998,7(11):2256-2264.
[6]Scott CP,Abel-Santos E,Wall M,et al.Production of cyclic peptides and proteins in vivo[J].Proc Natl Acad Sci USA,1999,96(24):13638-13643.
[7]Kee KS,Jois SD.Design of beta-turn based therapeutic agents[J].Curr Pharm Des,2003,9(15):1209-1224.
[8]Craik DJ,Simonsen S,Daly NL.The cyclotides:novel macrocyclic peptides as scaffolds in drug design[J].Curr Opin Drug Discov Dev,2002,5(2):251-260.
[9]Scott CP,Abel-Santos E,Jones AD,et al.Structural requirements for the biosynthesis of backbone cyclic peptide libraries[J].Chem Biol,2001,8(8):801-815.
[10]Perler FB.In Base:the intein database[J].Nucl Acids Res,2002,30(1):383-384.
[11]Starokadomskyy PL.Protein splicing[J].Mol Biol(Mosk),2007,41(2):314-330.
[12]Elleuche S,Pggeler S.Trans-splicing of an artificially split fungal mini-intein[J].Biochem Biophys Res Commun,2007,355(3):830-834.
[13]Poulter RT,Goodwin TJ,Butler MI.The nuclear-encoded inteins of fungi[J].Fungal Genet Biol,2007,44(3):153-179.
[14]Douglas SE,Penny SL.The plastid genome of the cryptophyte alga,Guillardiatheta:complete sequence and conserved synteny groups confirm its common ancestry with red algae[J].J Mol Evol,1999,48(2):236-344.
[15]Luo J,Hall BD.A multistep process gave rise to RNA polymeraseⅣof land plants[J].J Mol Evol,2007,64(1):101-112.
[16]Turmel M,Brouard JS,Gagnon C,et al.Deep division in the Chlorophyceae(Chlorophyta)revealed by chloroplast phylogenomic analyses[J].J Phycol,2008,44(3):739-750.
[17]Wang S,Liu XQ.Identification of an unusual intein in chloroplast Clp P protease of Chlamydomonas eugametos[J].J Biol Chem,1997,272(18):11869-11873.
[18]Liu XQ.Protein-splicing intein:genetic mobility,origin,and evolution[J].Ann Rev Genet,2000,34:61-76.
[19]Belfort M,Derbyshire V,Stoddard BL,et al.Homing Endonucleases and Inteins[M].New York,Berlin and Heidelberg:Springer Verlag,2005.
[20]Cheriyan M,Perler FB.Protein splicing:a versatile tool for drug discovery[J].Adv Drug Deliv Rev,2009,61(11):899-907.
[21]Kent SB.Total chemical synthesis of proteins[J].Chem Soc Rev,2009,38(2):338-351.
[22]Erlanson DA,Chytil M,Verdine GL.The leucine zipper domain controls the orientation of AP-1 in the NFAT.AP-1.DNA complex[J].Chem Biol,1996,3(12):981-991.
[23]Paulus H.Protein splicing and related forms of protein autoprocessing[J].Annu Rev Biochem,2000,69:447-496.
[24]Muir TW.Semisynthesis of proteins by expressed protein ligation[J].Annu Rev Biochem,2003,72:249-289.
[25]Muralidharan V,Muir TW.Protein ligation:an enabling technology for the biophysical analysis of proteins[J].Nat Methods,2006,3(6):429-438.
[26]Camarero JA,Muir TW.Biosynthesis of a head-to-tail cyclized protein with improved biological activity[J].J Am Chem Soc,1999,121(23):5597-5598.
[27]Camarero JA,Fushman D,Sato S,et al.Rescuing a destabilized protein fold through backbone cyclization[J].J Mol Biol,2001,308(5):1045-1062.
[28]Iwai H,Pluckthum A.Circularβ-lactamase:stability enhancement by cyclizing the backbone[J].FEBS Lett,1999,459(2):166-172.
[29]Hirel PH,Schmitter MJ,Dessen P,et al.Extent of N-terminal methionine excision from Escherichia coli proteins is governed by the side-chain length of the penultimate amino acid[J].Proc Natl Acad Sci USA,1989,86(21):8247-8251.
[30]Craik DJ,Daly NL,Bond T,et al.Plant cyclotides:a unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif[J].J Mol Biol,1999,294(5):1327-1336.
[31]Greenwood KP,Daly NL,Brown DL,et al.The cyclic cystine knot miniprotein MCoT I-Ⅱis internalized into cells by macropinocytosis[J].Int J Biochem Cell Biol,2007,39(12):2252-2264.
[32]Camarero JA,Kimura RH,Woo YH,et al.Biosynthesis of a fully functional cyclotide inside living bacterial cells[J].Chembiochem,2007,8(12):1363-1366.
[33]Kimura RH,Tran AT,Camarero JA.Biosynthesis of the cyclotide Kalata B1 by using protein splicing[J].Angew Chem Int Ed Engl,2006,45(6):973-976.
[34]Austin J,Kimura RH,Woo YH,et al.In vivo biosynthesis of an Ala-scan library based on the cyclic peptide SFTI-1[J].Amino Acids,2010,38(5):1313-1322.
[35]Gould A,Li Y,Majumder S,et al.Recombinant production of rhesusθ-defensin-1(RTD-1)using a bacterial expression system[J].Mol Biosyst,2012,8(4):1359-1365.
[36]Garcia AE,Tai KP,Puttamadappa SS,et al.Biosynthesis and antimicrobial evaluation of backbone-cyclizedα-defensins[J].Biochemistry,2011,50(48):10508-10519.
[37]Vila-Perell M,Muir TW.Biological applications of protein splicing[J].Cell,2010,143(2):191-200.
[38]Saleh L,Perler FB.Protein splicing in cis and in trans[J].Chem Rec,2006,6(4):183-193.
[39]Xu MQ,Evans TC Jr.Recent advances in protein splicing:manipulating proteins in vitro and in vivo[J].Curr Opin Biotechnol,2005,16(4):440-446.
[40]Abel-Santos E,Scott CP,Benkovic SJ.Use of inteins for the in vivo production of stable cyclic peptide libraries in E.coli[J].Methods Mol Biol,2003,205:281-294.
[41]Tavassoli A,Benkovic SJ.Split-intein mediated circular ligation used in the synthesis of cyclic peptide libraries in E.coli[J].Natl Protoc,2007,2(5):1126-1133.
[42]Cheng L,Naumann TA,Horswill AR,et al.Discovery of antibacterial cyclic peptides that inhibit the Clp XP protease[J].Protein Sci,2007,16(8):1535-1542.
[43]Kritzer JA,Hamamichi S,McC affery JM,et al.Rapid selection of cyclic peptides that reduce alpha-synuclein toxicity in yeast and animal models[J].Nat Chem Biol,2009,5(9):655-663.
[44]Tavassoli A,Lu Q,Gam J,et al.Inhibition of HIV budding by a genetically selected cyclic peptide targeting the Gag TSG101 interaction[J].ACS Chem Biol,2008,3(12):757-764.
[45]Horswill AR,Savinov SN,Benkovic SJ.A systematic method for identifying small-molecule modulators of protein protein interactions[J].Proc Natl Acad Sci USA,2004,101(44):15591-15596.
[46]Tavassoli A,Benkovic SJ.Genetically selected cyclic-peptide inhibitors of AICAR transformylase homodimerization[J].Angew Chem Int Ed Engl,2005,44(18):2760-2763.
[47]Kanno A,Yamanaka Y,Hirano H,et al.Cyclic luciferase for real-time sensing of caspase-3 activities in living mammals[J].Angew Chem Int Ed Engl,2007,46(40):7595-7599.
[48]Kinsella TM,Ohashi CT,Harder AG,et al.Retrovirally delivered random cyclic peptide libraries yield inhibitors of interleukin-4 signaling in human B cells[J].J Biol Chem,2002,277(40):37512-37518.
[49]Li J,Sun W,Wang B,et al.Protein trans-splicing as a means for viral vector-mediated in vivo gene therapy[J].Hum Gene Ther,2008,19(9):958-964.
[50]Young TS,Young DD,Ahmad I,et al.Evolution of cyclic peptide protease inhibitors[J].Proc Natl Acad Sci USA,2011,108(27):11052-11056.
[51]Sudheer PD,Pack SP,Kang TJ.Cyclization tag for the detection and facile purification of backbone-cyclized proteins[J].Anal Biochem,2013,436(2):137-141.
[52]Zettler J,Schutz V,Mootz HD.The naturally split Npu Dna Eintein exhibits an extraordinarily high rate in the protein trans-splicing reaction[J].FEBS Lett,2009,583(5):909-914.
[53]叶丙雨,王政,李德彬,等.环式增强型绿色荧光蛋白热稳定性及Npu DnaE内含肽高反式剪接效率研究[J].军事医学,2012,36(4):253-257.
[54]Jagadish K,Borra R,Lacey V,et al.Expression of fluorescent cyclotides using protein trans-splicing for easy monitoring of cyclotide-protein interactions[J].Angew Chem Int Ed Engl,2013,52(11):3126-3131.
[55]Wong S,Mosabbir AA,Truong K.An engineered split intein for photoactivated protein trans-splicing[J].PLoS One,2015,10(8):e0135965.
[56]Sancheti H,Camarero JA.Cell-based expression and screening of genetically-encoded libraries of backbone-cyclized polypeptides[J].Adv Drug Deliv Rev,2009,61(11):908-917.
[2]Hirata R,Ohsumk Y,Nakano A,et al.Molecular structure of a gene,VMA1,encoding the catalytic subunit of H(+)-translocating adenosine triphosphatase from vacuolar membranes of Saccharomyces cerevisiae[J].J Biol Chem,1990,265(12):6726-6733.
[3]Perler FB,Davis EO,Dean GE,et al.Protein splicing elements:inteins and exteins,a definition of terms,and recommended nomenclature[J].Nucleic Acids Res,1994,22(7):1125-1127.
[4]Muir TW,Sondhi D,Cole PA.Expressed protein ligation:a general method for protein engineering[J].Proc Natl Acad Sci USA,1998,95(12):6705-6710.
[5]Evans TC Jr,Benner J,Xu MQ.Semisynthesis of cytotoxic proteins using a modified protein splicing element[J].Protein Sci,1998,7(11):2256-2264.
[6]Scott CP,Abel-Santos E,Wall M,et al.Production of cyclic peptides and proteins in vivo[J].Proc Natl Acad Sci USA,1999,96(24):13638-13643.
[7]Kee KS,Jois SD.Design of beta-turn based therapeutic agents[J].Curr Pharm Des,2003,9(15):1209-1224.
[8]Craik DJ,Simonsen S,Daly NL.The cyclotides:novel macrocyclic peptides as scaffolds in drug design[J].Curr Opin Drug Discov Dev,2002,5(2):251-260.
[9]Scott CP,Abel-Santos E,Jones AD,et al.Structural requirements for the biosynthesis of backbone cyclic peptide libraries[J].Chem Biol,2001,8(8):801-815.
[10]Perler FB.In Base:the intein database[J].Nucl Acids Res,2002,30(1):383-384.
[11]Starokadomskyy PL.Protein splicing[J].Mol Biol(Mosk),2007,41(2):314-330.
[12]Elleuche S,Pggeler S.Trans-splicing of an artificially split fungal mini-intein[J].Biochem Biophys Res Commun,2007,355(3):830-834.
[13]Poulter RT,Goodwin TJ,Butler MI.The nuclear-encoded inteins of fungi[J].Fungal Genet Biol,2007,44(3):153-179.
[14]Douglas SE,Penny SL.The plastid genome of the cryptophyte alga,Guillardiatheta:complete sequence and conserved synteny groups confirm its common ancestry with red algae[J].J Mol Evol,1999,48(2):236-344.
[15]Luo J,Hall BD.A multistep process gave rise to RNA polymeraseⅣof land plants[J].J Mol Evol,2007,64(1):101-112.
[16]Turmel M,Brouard JS,Gagnon C,et al.Deep division in the Chlorophyceae(Chlorophyta)revealed by chloroplast phylogenomic analyses[J].J Phycol,2008,44(3):739-750.
[17]Wang S,Liu XQ.Identification of an unusual intein in chloroplast Clp P protease of Chlamydomonas eugametos[J].J Biol Chem,1997,272(18):11869-11873.
[18]Liu XQ.Protein-splicing intein:genetic mobility,origin,and evolution[J].Ann Rev Genet,2000,34:61-76.
[19]Belfort M,Derbyshire V,Stoddard BL,et al.Homing Endonucleases and Inteins[M].New York,Berlin and Heidelberg:Springer Verlag,2005.
[20]Cheriyan M,Perler FB.Protein splicing:a versatile tool for drug discovery[J].Adv Drug Deliv Rev,2009,61(11):899-907.
[21]Kent SB.Total chemical synthesis of proteins[J].Chem Soc Rev,2009,38(2):338-351.
[22]Erlanson DA,Chytil M,Verdine GL.The leucine zipper domain controls the orientation of AP-1 in the NFAT.AP-1.DNA complex[J].Chem Biol,1996,3(12):981-991.
[23]Paulus H.Protein splicing and related forms of protein autoprocessing[J].Annu Rev Biochem,2000,69:447-496.
[24]Muir TW.Semisynthesis of proteins by expressed protein ligation[J].Annu Rev Biochem,2003,72:249-289.
[25]Muralidharan V,Muir TW.Protein ligation:an enabling technology for the biophysical analysis of proteins[J].Nat Methods,2006,3(6):429-438.
[26]Camarero JA,Muir TW.Biosynthesis of a head-to-tail cyclized protein with improved biological activity[J].J Am Chem Soc,1999,121(23):5597-5598.
[27]Camarero JA,Fushman D,Sato S,et al.Rescuing a destabilized protein fold through backbone cyclization[J].J Mol Biol,2001,308(5):1045-1062.
[28]Iwai H,Pluckthum A.Circularβ-lactamase:stability enhancement by cyclizing the backbone[J].FEBS Lett,1999,459(2):166-172.
[29]Hirel PH,Schmitter MJ,Dessen P,et al.Extent of N-terminal methionine excision from Escherichia coli proteins is governed by the side-chain length of the penultimate amino acid[J].Proc Natl Acad Sci USA,1989,86(21):8247-8251.
[30]Craik DJ,Daly NL,Bond T,et al.Plant cyclotides:a unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif[J].J Mol Biol,1999,294(5):1327-1336.
[31]Greenwood KP,Daly NL,Brown DL,et al.The cyclic cystine knot miniprotein MCoT I-Ⅱis internalized into cells by macropinocytosis[J].Int J Biochem Cell Biol,2007,39(12):2252-2264.
[32]Camarero JA,Kimura RH,Woo YH,et al.Biosynthesis of a fully functional cyclotide inside living bacterial cells[J].Chembiochem,2007,8(12):1363-1366.
[33]Kimura RH,Tran AT,Camarero JA.Biosynthesis of the cyclotide Kalata B1 by using protein splicing[J].Angew Chem Int Ed Engl,2006,45(6):973-976.
[34]Austin J,Kimura RH,Woo YH,et al.In vivo biosynthesis of an Ala-scan library based on the cyclic peptide SFTI-1[J].Amino Acids,2010,38(5):1313-1322.
[35]Gould A,Li Y,Majumder S,et al.Recombinant production of rhesusθ-defensin-1(RTD-1)using a bacterial expression system[J].Mol Biosyst,2012,8(4):1359-1365.
[36]Garcia AE,Tai KP,Puttamadappa SS,et al.Biosynthesis and antimicrobial evaluation of backbone-cyclizedα-defensins[J].Biochemistry,2011,50(48):10508-10519.
[37]Vila-Perell M,Muir TW.Biological applications of protein splicing[J].Cell,2010,143(2):191-200.
[38]Saleh L,Perler FB.Protein splicing in cis and in trans[J].Chem Rec,2006,6(4):183-193.
[39]Xu MQ,Evans TC Jr.Recent advances in protein splicing:manipulating proteins in vitro and in vivo[J].Curr Opin Biotechnol,2005,16(4):440-446.
[40]Abel-Santos E,Scott CP,Benkovic SJ.Use of inteins for the in vivo production of stable cyclic peptide libraries in E.coli[J].Methods Mol Biol,2003,205:281-294.
[41]Tavassoli A,Benkovic SJ.Split-intein mediated circular ligation used in the synthesis of cyclic peptide libraries in E.coli[J].Natl Protoc,2007,2(5):1126-1133.
[42]Cheng L,Naumann TA,Horswill AR,et al.Discovery of antibacterial cyclic peptides that inhibit the Clp XP protease[J].Protein Sci,2007,16(8):1535-1542.
[43]Kritzer JA,Hamamichi S,McC affery JM,et al.Rapid selection of cyclic peptides that reduce alpha-synuclein toxicity in yeast and animal models[J].Nat Chem Biol,2009,5(9):655-663.
[44]Tavassoli A,Lu Q,Gam J,et al.Inhibition of HIV budding by a genetically selected cyclic peptide targeting the Gag TSG101 interaction[J].ACS Chem Biol,2008,3(12):757-764.
[45]Horswill AR,Savinov SN,Benkovic SJ.A systematic method for identifying small-molecule modulators of protein protein interactions[J].Proc Natl Acad Sci USA,2004,101(44):15591-15596.
[46]Tavassoli A,Benkovic SJ.Genetically selected cyclic-peptide inhibitors of AICAR transformylase homodimerization[J].Angew Chem Int Ed Engl,2005,44(18):2760-2763.
[47]Kanno A,Yamanaka Y,Hirano H,et al.Cyclic luciferase for real-time sensing of caspase-3 activities in living mammals[J].Angew Chem Int Ed Engl,2007,46(40):7595-7599.
[48]Kinsella TM,Ohashi CT,Harder AG,et al.Retrovirally delivered random cyclic peptide libraries yield inhibitors of interleukin-4 signaling in human B cells[J].J Biol Chem,2002,277(40):37512-37518.
[49]Li J,Sun W,Wang B,et al.Protein trans-splicing as a means for viral vector-mediated in vivo gene therapy[J].Hum Gene Ther,2008,19(9):958-964.
[50]Young TS,Young DD,Ahmad I,et al.Evolution of cyclic peptide protease inhibitors[J].Proc Natl Acad Sci USA,2011,108(27):11052-11056.
[51]Sudheer PD,Pack SP,Kang TJ.Cyclization tag for the detection and facile purification of backbone-cyclized proteins[J].Anal Biochem,2013,436(2):137-141.
[52]Zettler J,Schutz V,Mootz HD.The naturally split Npu Dna Eintein exhibits an extraordinarily high rate in the protein trans-splicing reaction[J].FEBS Lett,2009,583(5):909-914.
[53]叶丙雨,王政,李德彬,等.环式增强型绿色荧光蛋白热稳定性及Npu DnaE内含肽高反式剪接效率研究[J].军事医学,2012,36(4):253-257.
[54]Jagadish K,Borra R,Lacey V,et al.Expression of fluorescent cyclotides using protein trans-splicing for easy monitoring of cyclotide-protein interactions[J].Angew Chem Int Ed Engl,2013,52(11):3126-3131.
[55]Wong S,Mosabbir AA,Truong K.An engineered split intein for photoactivated protein trans-splicing[J].PLoS One,2015,10(8):e0135965.
[56]Sancheti H,Camarero JA.Cell-based expression and screening of genetically-encoded libraries of backbone-cyclized polypeptides[J].Adv Drug Deliv Rev,2009,61(11):908-917.