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Proc Natl Acad Sci U S A. Oct 29, 1996; 93(22): 12142–12149.
PMCID: PMC37957

The N-end rule: functions, mysteries, uses.

Abstract

The N-end rule relates the in vivo half-life of a protein to the identity of its N-terminal residue. Similar but distinct versions of the N-end rule operate in all organisms examined, from mammals to fungi and bacteria. In eukaryotes, the N-end rule pathway is a part of the ubiquitin system. I discuss the mechanisms and functions of this pathway, and consider its applications.

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  • Lévy F, Johnsson N, Rümenapf T, Varshavsky A. Using ubiquitin to follow the metabolic fate of a protein. Proc Natl Acad Sci U S A. 1996 May 14;93(10):4907–4912. [PMC free article] [PubMed]
  • Baker RT, Varshavsky A. Inhibition of the N-end rule pathway in living cells. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1090–1094. [PMC free article] [PubMed]
  • Varshavsky A. Naming a targeting signal. Cell. 1991 Jan 11;64(1):13–15. [PubMed]
  • Bachmair A, Finley D, Varshavsky A. In vivo half-life of a protein is a function of its amino-terminal residue. Science. 1986 Oct 10;234(4773):179–186. [PubMed]
  • Varshavsky A. The N-end rule. Cell. 1992 May 29;69(5):725–735. [PubMed]
  • Varshavsky A. The N-end rule. Cold Spring Harb Symp Quant Biol. 1995;60:461–478. [PubMed]
  • Tobias JW, Shrader TE, Rocap G, Varshavsky A. The N-end rule in bacteria. Science. 1991 Nov 29;254(5036):1374–1377. [PubMed]
  • Bachmair A, Varshavsky A. The degradation signal in a short-lived protein. Cell. 1989 Mar 24;56(6):1019–1032. [PubMed]
  • Shrader TE, Tobias JW, Varshavsky A. The N-end rule in Escherichia coli: cloning and analysis of the leucyl, phenylalanyl-tRNA-protein transferase gene aat. J Bacteriol. 1993 Jul;175(14):4364–4374. [PMC free article] [PubMed]
  • Gonda DK, Bachmair A, Wünning I, Tobias JW, Lane WS, Varshavsky A. Universality and structure of the N-end rule. J Biol Chem. 1989 Oct 5;264(28):16700–16712. [PubMed]
  • Johnson ES, Gonda DK, Varshavsky A. cis-trans recognition and subunit-specific degradation of short-lived proteins. Nature. 1990 Jul 19;346(6281):287–291. [PubMed]
  • Schatz G, Dobberstein B. Common principles of protein translocation across membranes. Science. 1996 Mar 15;271(5255):1519–1526. [PubMed]
  • Nishizawa M, Furuno N, Okazaki K, Tanaka H, Ogawa Y, Sagata N. Degradation of Mos by the N-terminal proline (Pro2)-dependent ubiquitin pathway on fertilization of Xenopus eggs: possible significance of natural selection for Pro2 in Mos. EMBO J. 1993 Oct;12(10):4021–4027. [PMC free article] [PubMed]
  • Dohmen RJ, Wu P, Varshavsky A. Heat-inducible degron: a method for constructing temperature-sensitive mutants. Science. 1994 Mar 4;263(5151):1273–1276. [PubMed]
  • Chau V, Tobias JW, Bachmair A, Marriott D, Ecker DJ, Gonda DK, Varshavsky A. A multiubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science. 1989 Mar 24;243(4898):1576–1583. [PubMed]
  • Spence J, Sadis S, Haas AL, Finley D. A ubiquitin mutant with specific defects in DNA repair and multiubiquitination. Mol Cell Biol. 1995 Mar;15(3):1265–1273. [PMC free article] [PubMed]
  • Hershko A. The ubiquitin pathway for protein degradation. Trends Biochem Sci. 1991 Jul;16(7):265–268. [PubMed]
  • Jentsch S. The ubiquitin-conjugation system. Annu Rev Genet. 1992;26:179–207. [PubMed]
  • Hochstrasser M. Ubiquitin, proteasomes, and the regulation of intracellular protein degradation. Curr Opin Cell Biol. 1995 Apr;7(2):215–223. [PubMed]
  • Pahl HL, Baeuerle PA. Control of gene expression by proteolysis. Curr Opin Cell Biol. 1996 Jun;8(3):340–347. [PubMed]
  • Dohmen RJ, Madura K, Bartel B, Varshavsky A. The N-end rule is mediated by the UBC2(RAD6) ubiquitin-conjugating enzyme. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7351–7355. [PMC free article] [PubMed]
  • Madura K, Dohmen RJ, Varshavsky A. N-recognin/Ubc2 interactions in the N-end rule pathway. J Biol Chem. 1993 Jun 5;268(16):12046–12054. [PubMed]
  • Rechsteiner M, Hoffman L, Dubiel W. The multicatalytic and 26 S proteases. J Biol Chem. 1993 Mar 25;268(9):6065–6068. [PubMed]
  • Hilt W, Wolf DH. Proteasomes: destruction as a programme. Trends Biochem Sci. 1996 Mar;21(3):96–102. [PubMed]
  • Bartel B, Wünning I, Varshavsky A. The recognition component of the N-end rule pathway. EMBO J. 1990 Oct;9(10):3179–3189. [PMC free article] [PubMed]
  • Reiss Y, Kaim D, Hershko A. Specificity of binding of NH2-terminal residue of proteins to ubiquitin-protein ligase. Use of amino acid derivatives to characterize specific binding sites. J Biol Chem. 1988 Feb 25;263(6):2693–2698. [PubMed]
  • Wolf S, Lottspeich F, Baumeister W. Ubiquitin found in the archaebacterium Thermoplasma acidophilum. FEBS Lett. 1993 Jul 12;326(1-3):42–44. [PubMed]
  • Gottesman S, Maurizi MR. Regulation by proteolysis: energy-dependent proteases and their targets. Microbiol Rev. 1992 Dec;56(4):592–621. [PMC free article] [PubMed]
  • Baker RT, Varshavsky A. Yeast N-terminal amidase. A new enzyme and component of the N-end rule pathway. J Biol Chem. 1995 May 19;270(20):12065–12074. [PubMed]
  • Wickner S, Gottesman S, Skowyra D, Hoskins J, McKenney K, Maurizi MR. A molecular chaperone, ClpA, functions like DnaK and DnaJ. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12218–12222. [PMC free article] [PubMed]
  • Stewart AE, Arfin SM, Bradshaw RA. The sequence of porcine protein NH2-terminal asparagine amidohydrolase. A new component of the N-end Rule pathway. J Biol Chem. 1995 Jan 6;270(1):25–28. [PubMed]
  • Balzi E, Choder M, Chen WN, Varshavsky A, Goffeau A. Cloning and functional analysis of the arginyl-tRNA-protein transferase gene ATE1 of Saccharomyces cerevisiae. J Biol Chem. 1990 May 5;265(13):7464–7471. [PubMed]
  • Dayal VK, Chakraborty G, Sturman JA, Ingoglia NA. The site of amino acid addition to posttranslationally modified proteins of regenerating rat sciatic nerves. Biochim Biophys Acta. 1990 Apr 19;1038(2):172–177. [PubMed]
  • Scheffner M, Nuber U, Huibregtse JM. Protein ubiquitination involving an E1-E2-E3 enzyme ubiquitin thioester cascade. Nature. 1995 Jan 5;373(6509):81–83. [PubMed]
  • Arnason T, Ellison MJ. Stress resistance in Saccharomyces cerevisiae is strongly correlated with assembly of a novel type of multiubiquitin chain. Mol Cell Biol. 1994 Dec;14(12):7876–7883. [PMC free article] [PubMed]
  • Johnson ES, Ma PC, Ota IM, Varshavsky A. A proteolytic pathway that recognizes ubiquitin as a degradation signal. J Biol Chem. 1995 Jul 21;270(29):17442–17456. [PubMed]
  • Baboshina OV, Haas AL. Novel multiubiquitin chain linkages catalyzed by the conjugating enzymes E2EPF and RAD6 are recognized by 26 S proteasome subunit 5. J Biol Chem. 1996 Feb 2;271(5):2823–2831. [PubMed]
  • McGrath JP, Jentsch S, Varshavsky A. UBA 1: an essential yeast gene encoding ubiquitin-activating enzyme. EMBO J. 1991 Jan;10(1):227–236. [PMC free article] [PubMed]
  • Negrutskii BS, Deutscher MP. Channeling of aminoacyl-tRNA for protein synthesis in vivo. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4991–4995. [PMC free article] [PubMed]
  • Knighton DR, Kan CC, Howland E, Janson CA, Hostomska Z, Welsh KM, Matthews DA. Structure of and kinetic channelling in bifunctional dihydrofolate reductase-thymidylate synthase. Nat Struct Biol. 1994 Mar;1(3):186–194. [PubMed]
  • Ozkaynak E, Finley D, Solomon MJ, Varshavsky A. The yeast ubiquitin genes: a family of natural gene fusions. EMBO J. 1987 May;6(5):1429–1439. [PMC free article] [PubMed]
  • Finley D, Bartel B, Varshavsky A. The tails of ubiquitin precursors are ribosomal proteins whose fusion to ubiquitin facilitates ribosome biogenesis. Nature. 1989 Mar 30;338(6214):394–401. [PubMed]
  • Watkins JF, Sung P, Prakash L, Prakash S. The Saccharomyces cerevisiae DNA repair gene RAD23 encodes a nuclear protein containing a ubiquitin-like domain required for biological function. Mol Cell Biol. 1993 Dec;13(12):7757–7765. [PMC free article] [PubMed]
  • Li X, Chang YH. Amino-terminal protein processing in Saccharomyces cerevisiae is an essential function that requires two distinct methionine aminopeptidases. Proc Natl Acad Sci U S A. 1995 Dec 19;92(26):12357–12361. [PMC free article] [PubMed]
  • Arfin SM, Bradshaw RA. Cotranslational processing and protein turnover in eukaryotic cells. Biochemistry. 1988 Oct 18;27(21):7979–7984. [PubMed]
  • Sherman F, Stewart JW, Tsunasawa S. Methionine or not methionine at the beginning of a protein. Bioessays. 1985 Jul;3(1):27–31. [PubMed]
  • Sadis S, Atienza C, Jr, Finley D. Synthetic signals for ubiquitin-dependent proteolysis. Mol Cell Biol. 1995 Aug;15(8):4086–4094. [PMC free article] [PubMed]
  • Kaiser CA, Preuss D, Grisafi P, Botstein D. Many random sequences functionally replace the secretion signal sequence of yeast invertase. Science. 1987 Jan 16;235(4786):312–317. [PubMed]
  • Scherer DC, Brockman JA, Chen Z, Maniatis T, Ballard DW. Signal-induced degradation of I kappa B alpha requires site-specific ubiquitination. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11259–11263. [PMC free article] [PubMed]
  • Deveraux Q, Ustrell V, Pickart C, Rechsteiner M. A 26 S protease subunit that binds ubiquitin conjugates. J Biol Chem. 1994 Mar 11;269(10):7059–7061. [PubMed]
  • Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell. 1990 Dec 21;63(6):1129–1136. [PubMed]
  • Johnston JA, Johnson ES, Waller PR, Varshavsky A. Methotrexate inhibits proteolysis of dihydrofolate reductase by the N-end rule pathway. J Biol Chem. 1995 Apr 7;270(14):8172–8178. [PubMed]
  • Ota IM, Varshavsky A. A gene encoding a putative tyrosine phosphatase suppresses lethality of an N-end rule-dependent mutant. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2355–2359. [PMC free article] [PubMed]
  • Ota IM, Varshavsky A. A yeast protein similar to bacterial two-component regulators. Science. 1993 Oct 22;262(5133):566–569. [PubMed]
  • Maeda T, Wurgler-Murphy SM, Saito H. A two-component system that regulates an osmosensing MAP kinase cascade in yeast. Nature. 1994 May 19;369(6477):242–245. [PubMed]
  • Alagramam K, Naider F, Becker JM. A recognition component of the ubiquitin system is required for peptide transport in Saccharomyces cerevisiae. Mol Microbiol. 1995 Jan;15(2):225–234. [PubMed]
  • Knight SA, Tamai KT, Kosman DJ, Thiele DJ. Identification and analysis of a Saccharomyces cerevisiae copper homeostasis gene encoding a homeodomain protein. Mol Cell Biol. 1994 Dec;14(12):7792–7804. [PMC free article] [PubMed]
  • Ellis RE, Yuan JY, Horvitz HR. Mechanisms and functions of cell death. Annu Rev Cell Biol. 1991;7:663–698. [PubMed]
  • Aizenman E, Engelberg-Kulka H, Glaser G. An Escherichia coli chromosomal "addiction module" regulated by guanosine [corrected] 3',5'-bispyrophosphate: a model for programmed bacterial cell death. Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):6059–6063. [PMC free article] [PubMed]
  • Kayalar C, Ord T, Testa MP, Zhong LT, Bredesen DE. Cleavage of actin by interleukin 1 beta-converting enzyme to reverse DNase I inhibition. Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):2234–2238. [PMC free article] [PubMed]
  • Emoto Y, Manome Y, Meinhardt G, Kisaki H, Kharbanda S, Robertson M, Ghayur T, Wong WW, Kamen R, Weichselbaum R, et al. Proteolytic activation of protein kinase C delta by an ICE-like protease in apoptotic cells. EMBO J. 1995 Dec 15;14(24):6148–6156. [PMC free article] [PubMed]
  • Thornberry NA, Bull HG, Calaycay JR, Chapman KT, Howard AD, Kostura MJ, Miller DK, Molineaux SM, Weidner JR, Aunins J, et al. A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature. 1992 Apr 30;356(6372):768–774. [PubMed]
  • Madura K, Varshavsky A. Degradation of G alpha by the N-end rule pathway. Science. 1994 Sep 2;265(5177):1454–1458. [PubMed]
  • Levis MJ, Bourne HR. Activation of the alpha subunit of Gs in intact cells alters its abundance, rate of degradation, and membrane avidity. J Cell Biol. 1992 Dec;119(5):1297–1307. [PMC free article] [PubMed]
  • Strauss JH, Strauss EG. The alphaviruses: gene expression, replication, and evolution. Microbiol Rev. 1994 Sep;58(3):491–562. [PMC free article] [PubMed]
  • de Groot RJ, Rümenapf T, Kuhn RJ, Strauss EG, Strauss JH. Sindbis virus RNA polymerase is degraded by the N-end rule pathway. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):8967–8971. [PMC free article] [PubMed]
  • Dougherty WG, Semler BL. Expression of virus-encoded proteinases: functional and structural similarities with cellular enzymes. Microbiol Rev. 1993 Dec;57(4):781–822. [PMC free article] [PubMed]
  • Nishizawa M, Okazaki K, Furuno N, Watanabe N, Sagata N. The 'second-codon rule' and autophosphorylation govern the stability and activity of Mos during the meiotic cell cycle in Xenopus oocytes. EMBO J. 1992 Jul;11(7):2433–2446. [PMC free article] [PubMed]
  • Watanabe N, Hunt T, Ikawa Y, Sagata N. Independent inactivation of MPF and cytostatic factor (Mos) upon fertilization of Xenopus eggs. Nature. 1991 Jul 18;352(6332):247–248. [PubMed]
  • Wiertz EJ, Jones TR, Sun L, Bogyo M, Geuze HJ, Ploegh HL. The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell. 1996 Mar 8;84(5):769–779. [PubMed]
  • Hiller MM, Finger A, Schweiger M, Wolf DH. ER degradation of a misfolded luminal protein by the cytosolic ubiquitin-proteasome pathway. Science. 1996 Sep 20;273(5282):1725–1728. [PubMed]
  • Park EC, Finley D, Szostak JW. A strategy for the generation of conditional mutations by protein destabilization. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1249–1252. [PMC free article] [PubMed]
  • Cormack BP, Struhl K. The TATA-binding protein is required for transcription by all three nuclear RNA polymerases in yeast cells. Cell. 1992 May 15;69(4):685–696. [PubMed]
  • Varshavsky A. Codominance and toxins: a path to drugs of nearly unlimited selectivity. Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3663–3667. [PMC free article] [PubMed]

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