Nedd8

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Nedd8
Nedd8
PDB  1NDD

Existing structure data : PDB  1R4M , PDB  1R4N

Properties of human protein
Mass / length primary structure 81 amino acids , 9,072 Da
Identifier
External IDs
Orthologue
human Baker's yeast
Entrez 4738 851717
Ensemble ENSG00000129559
UniProt Q15843 Q03919
Refseq (mRNA) NM_006156.3 NM_001180446.3
Refseq (protein) NP_006147.1 NP_010423.4
Gene locus
PubMed search 4738 851717

Nedd8 ( neural-precursor-cell-expressed developmentally down-regulated 8 'neural precursor cell-expressed and down-regulated in development 8') is a protein . It is attached to other proteins as a post-translational modification in the course of neddylation (for which Nedd8 is named) . This controls various processes in a cell . In baker's yeast ( Saccharomyces cerevisiae ), Nedd8 (more precisely: its homolog ) is called Rub1 .

properties

Nedd8 is a ubiquitin- like protein that is involved in the cell cycle and in embryogenesis . Neddylation is involved in various cellular processes, e.g. B. in the regulation of the ubiquitin-proteasome system , in the transcription , in cell contacts and in the global genome repair / nucleotide excision repair variant and the non-homologous end joining of DNA repair .

Nedd8 is covalently attached to other proteins through a ubiquitin-like enzyme cascade . The corresponding E1 enzyme is UBE1C - APPBP1 , the E2 enzyme is UBE2M . Human NEDD8 is 60% identical to ubiquitin in the amino acid sequence . The main target proteins are the cullins , which are a protein subunit of the cullin-dependent E3 ubiquitin protein ligases ( cullin-RING ubiquitin ligases , CRL). Neddylation takes place via an isopeptide bond on the carboxy group of the C -terminal glycine of Nedd8 to the ε- amino group of a lysine in the target protein. The binding of NEDD8 to Culline leads to activation of the E3 ubiquitin protein ligase function and to ubiquitination of the target protein. The labeled protein (for example cyclins ) is supplied to the ubiquitin proteasome system and broken down . Nedd8 is acetylated . The chemotherapeutic agent MLN4924 (synonym Pevonedistat ) is an inhibitor of the binding of Nedd8 to Culline. The proteases UCHL1, UCHL3 and USP21 can split off both NEDD8 and ubiquitin. The COP9 signalosome can specifically cleave Nedd8 from the Cullin-1 subunit of SCF ubiquitin ligases and NEDP1 (synonym DEN1, SENP8).

Incorrect neddylation is implicated in cancer , neurodegenerative diseases, and heart disease, among other things .

Individual evidence

  1. ↑ a b c d e f NEDD8 - NEDD8 precursor - Homo sapiens (Human) - NEDD8 gene & protein. In: uniprot.org. February 13, 2019, accessed March 12, 2019 .
  2. ↑ a b c d S. Kandala, IM Kim, H. Su: Neddylation and deneddylation in cardiac biology. In: American journal of cardiovascular disease. Volume 4, number 4, 2014, pp. 140-158, PMID 25628956 , PMC 4299693 (free full text).
  3. ^ R. Groisman, J. Polanowska, I. Kuraoka, J. Sawada, M. Saijo, R. Drapkin, AF Kisselev, K. Tanaka, Y. Nakatani: The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. In: Cell . Volume 113, Number 3, May 2003, pp. 357-367, PMID 12732143 .
  4. ↑ a b J. S. Brown, N. Lukashchuk, M. Sczaniecka-Clift, S. Britton, C. le Sage, P. Calsou, P. Beli, Y. Galanty, SP Jackson: Neddylation promotes ubiquitylation and release of Ku from DNA- damage sites. In: Cell Reports. Volume 11, number 5, May 2015, pp. 704-714, doi : 10.1016 / j.celrep.2015.03.058 , PMID 25921528 , PMC 4431666 (free full text).
  5. ↑ ZQ Pan, A. Kentsis, DC Dias, K. Yamoah, K. Wu: Nedd8 on cullin: building an expressway to protein destruction. In: Oncogene . Volume 23, Number 11, March 2004, pp. 1985-1997, doi : 10.1038 / sj.onc.1207414 , PMID 15021886 .
  6. ↑ NM Czuczman, MJ Barth, J. Gu, V. Neppalli, C. Mavis, SE Frys, Q. Hu, S. Liu, P. Klener, P. Vockova, MS Czuczman, FJ Hernandez-Ilizaliturri: Pevonedistat, a NEDD8 -activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo. In: Blood. Volume 127, number 9, March 2016, pp. 1128-1137, doi : 10.1182 / blood-2015-04-640920 , PMID 26675347 , PMC 4778163 (free full text).
  7. ^ Y. Chen, RL Neve, H. Liu: Neddylation dysfunction in Alzheimer's disease. In: Journal of cellular and molecular medicine. Volume 16, number 11, November 2012, pp. 2583-2591, doi : 10.1111 / j.1582-4934.2012.01604.x , PMID 22805479 , PMC 3484225 (free full text).