N -End Rule
The N -End Rule describes the influence of the N -terminal amino acid of a protein on its rate of degradation . This connection was first described in 1986 by a working group led by the Russian-American biochemist Alexander Varshavsky at the Massachusetts Institute of Technology .
properties
The N -terminal amino acid influences the proteolytic degradation of a protein. In protein biosynthesis , all proteins from eukaryotes or archaea are formed with a methionine as the first amino acid or with a formyl methionine in bacteria . Proteins with an N -terminal amino acid other than methionine can then be formed either by proteolysis or by removing the methionine by methionine aminopeptidases , provided that the subsequent amino acid is valine , glycine , proline , alanine , serine , threonine or cysteine . Of these seven amino acids, however, only cysteine leads to accelerated degradation.
Two types of N -terminal amino acids are recognized and subjected to proteolysis. These two types are known as degrons . The type 1 degron comprises basic amino acids ( arginine , lysine and histidine ) and the type 2 degron consists of aromatic and aliphatic amino acids ( phenylalanine , tyrosine , tryptophan , leucine and isoleucine ). In bacteria, recognition is carried out by the protein ClpS , which breaks down a protein with corresponding N- terminal amino acids by ClpAP . In eukaryotes, these two types of Degron are recognized by four types of recognins , which lead a bound protein to the E3 ubiquitin protein ligase and thus a breakdown in the ubiquitin proteasome system .
The arginylation of N -terminal aspartate , glutamate and cysteine sulfonic acid residues of a protein, which precedes degradation , takes place in eukaryotes by the arginine-tRNA protein transferase Ate1 . The cysteine sulfonic acid is an oxidized cysteine and is formed e.g. B. due to oxidation by nitric oxide or superoxide during the immune reaction . Aspartic acid and glutamic acid may be prepared by two different amidohydrolases to aspartate or glutamate deaminated and are subsequently provided with arginine. These N -terminal arginylated proteins are recognized by the recognins based on the type 1 degron (arginine) and supplied to the ubiquitin ligase.
The oxidation of cysteine to cysteine sulfonic acid is a sensor for cellular stress. As a result of the breakdown of the oxidized protein in the proteasome following the arginylation, proapoptotic proteins and peptides with oxidized cysteines are broken down, which initiate cell death if they are excessively accumulated. In the case of proteins of human pathogens , increased degradation by the N -terminal amino acids has been shown, e.g. B. in the integrase of HIV and in the Listeriolysin O of Listeria monocytogenes .
Biological half-lives of N -terminal amino acids
Depending on the species and the amino acid in the N -terminal position, these have different half-lives :
species | amino acid | Half-life | ||
Escherichia coli |
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Saccharomyces cerevisiae (baker's yeast) |
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Mammals |
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literature
- JH Lee, Y. Jiang et al. a .: Pharmacological Modulation of the N-End Rule Pathway and Its Therapeutic Implications. In: Trends in pharmacological sciences. Volume 36, number 11, November 2015, pp. 782-797, doi: 10.1016 / j.tips.2015.07.004 , PMID 26434644 , PMC 4641009 (free full text) (review).
- A. Varshavsky: The N-end rule pathway and regulation by proteolysis. In: Protein science. Volume 20, number 8, August 2011, pp. 1298-1345, doi: 10.1002 / pro.666 , PMID 21633985 , PMC 3189519 (free full text) (review).
- E. Graciet, F. Wellmer: The plant N-end rule pathway: structure and functions. In: Trends in plant science. Volume 15, Number 8, August 2010, pp. 447-453, doi: 10.1016 / j.tplants.2010.04.011 , PMID 20627801 (review).
- DA Dougan, KN Truscott, K. Zeth: The bacterial N-end rule pathway: expect the unexpected. In: Molecular microbiology. Volume 76, Number 3, May 2010, pp. 545-558, doi: 10.1111 / j.1365-2958.2010.07120.x , PMID 20374493 (review).
- Varshavsky, A.: The N-end rule and regulation of apoptosis. In: Nature cell biology. Volume 5, Number 5, May 2003, pp. 373-376, doi: 10.1038 / ncb0503-373 , PMID 12724766 (review).
- A. Varshavsky: The N-end rule: functions, mysteries, uses. In: Proceedings of the National Academy of Sciences . Volume 93, Number 22, October 1996, pp. 12142-12149, PMID 8901547 , PMC 37957 (free full text) (review).
- RT Baker, A. Varshavsky: Inhibition of the N-end rule pathway in living cells. In: PNAS. Volume 88, Number 4, February 1991, pp. 1090-1094, PMID 1899923 , PMC 50962 (free full text).
- DK Gonda, A. Bachmair et al. a .: Universality and structure of the N-end rule. In: The Journal of biological chemistry. Volume 264, Number 28, October 1989, pp. 16700-16712, PMID 2506181 .
- A. Varshavsky, A. Bachmair, D. Finley: The N-end rule of selective protein turnover: mechanistic aspects and functional implications. In: Biochemical Society transactions. Volume 15, Number 5, October 1987, pp. 815-816, PMID 3691950 .
- Konstantin I. Piatkov, Christopher S. Brower, Alexander Varshavsky: The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments . In: Proceedings of the National Academy of Sciences . tape 109 , no. 27 , 2012, p. E1839 – E1847 , doi : 10.1073 / pnas.1207786109 , PMID 22670058 (free full text).
Individual evidence
- ↑ Andreas Bachmair, Daniel Finley, Alexander Varshavsky: In vivo half-life of a protein is a function of its amino-terminal residue. In: Science . Volume 234, Number 4773, October 1986, pp. 179-186, PMID 3018930 .
- ↑ Quick or slow ends for proteins. In: New Scientist. dated Oct. 30, 1986, ISSN 0262-4079 , Volume 112, No. 1532, p. 25 ( limited preview in Google book search).
- ↑ a b c d e f g S. M. Sriram, R. Banerjee, RS Kane, YT Kwon: Multivalency-assisted control of intracellular signaling pathways: application for ubiquitin-dependent N-end rule pathway. In: Chem Biol. (2009), Volume 16 (2), pp. 121-131. doi: 10.1016 / j.chembiol.2009.01.012 . PMID 19246002 ; PMC 2665046 (free full text).
- ^ DA Dougan, KN Truscott, K. Zeth: The bacterial N-end rule pathway: expect the unexpected. In: Mol Microbiol. (2010), Volume 76 (3), pp. 545-558. doi: 10.1111 / j.1365-2958.2010.07120.x . PMID 20374493 .
- ↑ RG Hu, J. Sheng, X. Qi, Z. Xu, TT Takahashi, A. Varshavsky: The N-end rule pathway as a nitric oxide sensor controlling the levels of multiple regulators. In: Nature (2005), vol. 437 (7061), pp. 981-986. PMID 16222293 . PDF .
- ↑ KI Piatkov, CS Brower, A. Varshavsky : The N-end rule pathway counteracts cell death by destroying proapoptotic protein fragments. In: Proc Natl Acad Sci USA (2012), Volume 109 (27), pp. E1839-47. doi: 10.1073 / pnas.1207786109 . PMID 22670058 ; PMC 3390858 (free full text).
- ^ A b A. Varshavsky: The N-end rule pathway of protein degradation. In: Genes Cells. (1997), Vol. 2 (1), pp. 13-28. PMID 9112437 . PDF .
- ^ DK Gonda et al .: Universality and Structure of the N-end Rule. In: Journal of Biological Chemistry (1989), Volume 264: 28, pp. 16700-16712, PMID 2506181 .