title: Strategies for protein synthetic biology.
abstract: Proteins are the most versatile among the various biological building blocks and a mature field of protein engineering has lead to many industrial and biomedical applications. But the strength of proteins-their versatility, dynamics and interactions-also complicates and hinders systems engineering. Therefore, the design of more sophisticated, multi-component protein systems appears to lag behind, in particular, when compared to the engineering of gene regulatory networks. Yet, synthetic biologists have started to tinker with the information flow through natural signaling networks or integrated protein switches. A successful strategy common to most of these experiments is their focus on modular interactions between protein domains or domains and peptide motifs. Such modular interaction swapping has rewired signaling in yeast, put mammalian cell morphology under the control of light, or increased the flux through a synthetic metabolic pathway. Based on this experience, we outline an engineering framework for the connection of reusable protein interaction devices into self-sufficient circuits. Such a framework should help to 'refacture' protein complexity into well-defined exchangeable devices for predictive engineering. We review the foundations and initial success stories of protein synthetic biology and discuss the challenges and promises on the way from protein- to protein systems design.
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), UPF, 08003 Barcelona, Spain. raik.gruenberg@crg.es
authors.forename: Raik
authors.initials: R
authors.lastname: Grünberg
authors.forename: Luis
authors.initials: L
authors.lastname: Serrano
mesh_terms: D004247:DNA / Q000737:chemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D015202:Protein Engineering / Q000379:methods*; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D004247:DNA
references.citation: Nat Biotechnol. 2006 May;24(5):545-54
references.pmid: 16680139
references.citation: Curr Opin Struct Biol. 2008 Oct;18(5):630-40
references.pmid: 18721882
references.citation: Proc Natl Acad Sci U S A. 1998 Oct 13;95(21):12141-6
references.pmid: 9770453
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 23;106(25):10159-64
references.pmid: 19502422
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):16916-21
references.pmid: 17942691
references.citation: FEBS Lett. 1999 Dec 3;462(3):387-91
references.pmid: 10622731
references.citation: Nat Protoc. 2006;1(1):92-7
references.pmid: 17406217
references.citation: Nat Biotechnol. 2001 Nov;19(11):1042-6
references.pmid: 11689849
references.citation: Curr Opin Struct Biol. 2009 Aug;19(4):442-8
references.pmid: 19473830
references.citation: Chem Rev. 2000 Jul 12;100(7):2693-704
references.pmid: 11749301
references.citation: Chem Biol. 2009 Mar 27;16(3):249-54
references.pmid: 19318206
references.citation: J Biol Eng. 2009 Mar 20;3:4
references.pmid: 19298678
references.citation: Nat Methods. 2006 Dec;3(12):969-71
references.pmid: 17117150
references.citation: Curr Biol. 2001 Nov 27;11(23):1815-24
references.pmid: 11728304
references.citation: Proc Natl Acad Sci U S A. 1994 Oct 25;91(22):10340-4
references.pmid: 7937952
references.citation: Nature. 2009 Oct 15;461(7266):997-1001
references.pmid: 19749742
references.citation: Genes Dev. 2007 Sep 15;21(18):2271-6
references.pmid: 17875664
references.citation: Science. 2003 Apr 18;300(5618):445-52
references.pmid: 12702867
references.citation: Nat Biotechnol. 2002 Jun;20(6):619-22
references.pmid: 12042868
references.citation: Cell Signal. 2006 Jan;18(1):123-34
references.pmid: 15979847
references.citation: Trends Cell Biol. 2009 Aug;19(8):364-74
references.pmid: 19651513
references.citation: Nat Cell Biol. 2007 Nov;9(11):1319-26
references.pmid: 17952059
references.citation: Science. 1997 Dec 19;278(5346):2075-80
references.pmid: 9405336
references.citation: Biochim Biophys Acta. 2007 Aug;1773(8):1311-40
references.pmid: 17604854
references.citation: Science. 2006 Dec 1;314(5804):1454-7
references.pmid: 16990515
references.citation: Mol Syst Biol. 2006;2:2006.0028
references.pmid: 16738572
references.citation: J Mol Biol. 2004 Feb 6;336(1):263-73
references.pmid: 14741221
references.citation: Nat Biotechnol. 2002 Oct;20(10):1041-4
references.pmid: 12219076
references.citation: J Mol Biol. 2009 Feb 6;385(5):1433-44
references.pmid: 19109976
references.citation: Trends Biotechnol. 2005 Apr;23(4):199-207
references.pmid: 15780712
references.citation: Chem Biol. 2009 Mar 27;16(3):298-310
references.pmid: 19318211
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9517-22
references.pmid: 15972812
references.citation: J Mol Biol. 2008 Mar 7;376(5):1282-304
references.pmid: 18222472
references.citation: Curr Opin Biotechnol. 2005 Aug;16(4):459-69
references.pmid: 16005204
references.citation: Mol Cell. 2005 Oct 7;20(1):21-32
references.pmid: 16209942
references.citation: Mol Syst Biol. 2009;5:238
references.pmid: 19156130
references.citation: Mol Cell. 2008 Sep 26;31(6):925-32
references.pmid: 18922474
references.citation: Nature. 2000 Jan 20;403(6767):335-8
references.pmid: 10659856
references.citation: Nature. 1995 Jun 15;375(6532):549-54
references.pmid: 7791871
references.citation: Science. 2007 Nov 16;318(5853):1121-5
references.pmid: 18006742
references.citation: Annu Rev Biophys Biomol Struct. 2007;36:151-69
references.pmid: 17477838
references.citation: Biochem Biophys Res Commun. 2007 Mar 30;355(1):143-8
references.pmid: 17291454
references.citation: Structure. 2004 Dec;12(12):2125-36
references.pmid: 15576027
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10618-23
references.pmid: 9380684
references.citation: Mol Syst Biol. 2009;5:272
references.pmid: 19455136
references.citation: Annu Rev Cell Dev Biol. 2002;18:421-62
references.pmid: 12142282
references.citation: Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10266-71
references.pmid: 15240892
references.citation: Curr Opin Struct Biol. 2008 Apr;18(2):178-84
references.pmid: 18302984
references.citation: Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):7825-30
references.pmid: 9223271
references.citation: Mol Cell Biol. 2004 May;24(10):4294-308
references.pmid: 15121849
references.citation: Trends Biochem Sci. 2009 Oct;34(10):471-82
references.pmid: 19744855
references.citation: Nat Biotechnol. 2006 Jul;24(7):769-76
references.pmid: 16841057
references.citation: Nat Methods. 2006 Dec;3(12):985-93
references.pmid: 17072307
references.citation: Nucleic Acids Res. 1995 Sep 11;23(17):3605-6
references.pmid: 7567477
references.citation: J Mol Biol. 2009 Dec 4;394(3):391-409
references.pmid: 19733184
references.citation: Proteins. 2009;77 Suppl 9:1-4
references.pmid: 19774620
references.citation: Nucleic Acids Res. 2008 Aug;36(13):e78
references.pmid: 18559359
references.citation: Protein Eng Des Sel. 2010 Apr;23(4):251-60
references.pmid: 20083493
references.citation: J Biol Chem. 2007 Aug 10;282(32):23015-24
references.pmid: 17483489
references.citation: J Biol Eng. 2008 Apr 14;2:5
references.pmid: 18410688
references.citation: Curr Opin Struct Biol. 2006 Feb;16(1):118-26
references.pmid: 16434184
references.citation: Science. 2003 Feb 14;299(5609):1061-4
references.pmid: 12511654
references.citation: Nat Protoc. 2007;2(4):924-32
references.pmid: 17446874
references.citation: PLoS One. 2009 Sep 14;4(9):e7002
references.pmid: 19759823
references.citation: Curr Biol. 2007 Apr 17;17(8):668-77
references.pmid: 17398098
references.citation: Curr Opin Struct Biol. 2009 Apr;19(2):120-7
references.pmid: 19361980
references.citation: Curr Protein Pept Sci. 2008 Feb;9(1):1-15
references.pmid: 18336319
references.citation: Structure. 2006 Apr;14(4):683-93
references.pmid: 16615910
references.citation: Curr Opin Chem Biol. 2008 Apr;12(2):151-8
references.pmid: 18284924
references.citation: Hum Gene Ther. 2003 Nov 20;14(17):1619-29
references.pmid: 14633404
references.citation: Annu Rev Immunol. 1998;16:569-92
references.pmid: 9597142
references.citation: Curr Biol. 2008 Aug 26;18(16):1184-91
references.pmid: 18722124
references.citation: J Biol Chem. 2008 Mar 28;283(13):8469-76
references.pmid: 18230610
references.citation: EMBO J. 2001 May 15;20(10):2528-35
references.pmid: 11350942
references.citation: PLoS One. 2008 Aug 27;3(8):e3068
references.pmid: 18728784
references.citation: Nat Biotechnol. 2003 May;21(5):539-45
references.pmid: 12692560
references.citation: J Am Chem Soc. 2007 Apr 18;129(15):4606-11
references.pmid: 17381089
references.citation: Curr Biol. 1999 Apr 8;9(7):351-60
references.pmid: 10209117
references.citation: Science. 2008 Oct 3;322(5898):104-10
references.pmid: 18719252
references.citation: J Virol. 1988 Aug;62(8):2636-43
references.pmid: 2839690
references.citation: Mol Syst Biol. 2009;5:270
references.pmid: 19455134
references.citation: Science. 2009 Apr 10;324(5924):255-8
references.pmid: 19359587
references.citation: Nat Methods. 2005 Jun;2(6):415-8
references.pmid: 15908919
references.citation: Nat Cell Biol. 2001 Dec;3(12):1114-9
references.pmid: 11781573
references.citation: Nature. 1989 Jul 20;340(6230):245-6
references.pmid: 2547163
references.citation: Chembiochem. 2004 Feb 6;5(2):170-6
references.pmid: 14760737
references.citation: Nat Methods. 2007 Mar;4(3):251-6
references.pmid: 17293868
references.citation: Science. 2003 Sep 26;301(5641):1904-8
references.pmid: 14512628
references.citation: Sci Transl Med. 2010 Feb 3;2(17):17ps5
references.pmid: 20371477
references.citation: Trends Biochem Sci. 2009 Feb;34(2):60-70
references.pmid: 19101147
references.citation: Nat Methods. 2008 Feb;5(2):135-46
references.pmid: 18235434
references.citation: Mol Syst Biol. 2007;3:134
references.pmid: 17882154
references.citation: Nature. 2000 Jan 20;403(6767):339-42
references.pmid: 10659857
references.citation: Science. 2007 Jan 5;315(5808):115-9
references.pmid: 17204654
references.citation: Annu Rev Biophys. 2009;38:371-83
references.pmid: 19416074
references.citation: Nat Cell Biol. 2001 Dec;3(12):1051-9
references.pmid: 11781566
references.citation: Nature. 2007 May 31;447(7144):596-600
references.pmid: 17515921
references.citation: Curr Biol. 1996 Jul 1;6(7):839-47
references.pmid: 8805308
references.citation: Nat Biotechnol. 2009 Aug;27(8):753-9
references.pmid: 19648908
references.citation: Trends Biochem Sci. 1996 Nov;21(11):418-22
references.pmid: 8987395
references.citation: Front Biosci. 2008 May 01;13:6580-603
references.pmid: 18508681
references.citation: Nature. 2005 Nov 24;438(7067):449-53
references.pmid: 16306983
references.citation: Protein Eng Des Sel. 2009 Sep;22(9):537-42
references.pmid: 19574296
references.citation: J Am Chem Soc. 2005 Apr 6;127(13):4715-21
references.pmid: 15796538
references.citation: Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12288-93
references.pmid: 15284440
references.citation: PLoS One. 2007 Oct 03;2(10):e977
references.pmid: 17912354
references.citation: Nature. 2000 Jun 1;405(6786):590-3
references.pmid: 10850721
references.citation: Science. 2008 Mar 7;319(5868):1387-91
references.pmid: 18323453
references.citation: Nat Biotechnol. 2008 Jul;26(7):787-93
references.pmid: 18612302
references.citation: Mol Biol Cell. 2007 Dec;18(12):4945-56
references.pmid: 17914055
references.citation: Proc Natl Acad Sci U S A. 1996 May 14;93(10):4604-7
references.pmid: 8643450
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10709-14
references.pmid: 18667691
references.citation: Biochemistry. 1996 Apr 16;35(15):5083-92
references.pmid: 8664301
references.citation: FEBS Lett. 2005 Jun 13;579(15):3342-5
references.pmid: 15943979
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10437-42
references.pmid: 9724721
references.citation: Protein Eng Des Sel. 2009 Oct;22(10):615-23
references.pmid: 19622545
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11267-72
references.pmid: 13679576
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11511-2
references.pmid: 17606901
references.citation: Science. 2008 Mar 14;319(5869):1539-43
references.pmid: 18339942
references.citation: Nat Methods. 2008 Apr;5(4):303-5
references.pmid: 18272963
references.citation: Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11224-9
references.pmid: 16061816
references.citation: Sci Signal. 2009 Mar 03;2(60):pe11
references.pmid: 19261595
references.citation: Nat Biotechnol. 2009 Oct;27(10):946-50
references.pmid: 19801975
references.citation: Mol Syst Biol. 2008;4:191
references.pmid: 18463615
references.citation: J Am Chem Soc. 2003 Sep 3;125(35):10561-9
references.pmid: 12940738
references.citation: Nat Biotechnol. 2007 Jun;25(6):660-2
references.pmid: 17515908
references.citation: J Biotechnol. 2007 Sep 30;131(4):433-9
references.pmid: 17826857
references.citation: Biotechniques. 2007 Feb;42(2):137, 139, 141 passim
references.pmid: 17373475
references.citation: PLoS One. 2009 Oct 15;4(10):e7474
references.pmid: 19830250
references.citation: Genes Dev. 1998 Sep 1;12(17):2684-97
references.pmid: 9732267
references.citation: Analyst. 2008 May;133(5):571-84
references.pmid: 18427676
references.citation: Nature. 2008 May 8;453(7192):190-5
references.pmid: 18354394