• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Mar 28, 1995; 92(7): 2563–2567.
PMCID: PMC42258

A family of proteins structurally and functionally related to the E6-AP ubiquitin-protein ligase.

Abstract

E6-AP is a 100-kDa cellular protein that interacts with the E6 protein of the cancer-associated human papillomavirus types 16 and 18. The E6/E6-AP complex binds to and targets the p53 tumor-suppressor protein for ubiquitin-mediated proteolysis. E6-AP is an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. The amino acid sequence of E6-AP shows similarity to a number of protein sequences over an approximately 350-aa region corresponding to the carboxyl termini of both E6-AP and the E6-AP-related proteins. Of particular note is a conserved cysteine residue within the last 32-34 aa, which in E6-AP is likely to be the site of ubiquitin thioester formation. Two of the E6-AP-related proteins, a rat 100-kDa protein and a yeast 95-kDa protein (RSP5), both of previously unknown function, are shown here to form thioesters with ubiquitin. Mutation of the conserved cysteine residue of these proteins destroys their ability to accept ubiquitin. These data strongly suggest that the rat 100-kDa protein and RSP5, as well as the other E6-AP-related proteins, belong to a class of functionally related E3 ubiquitin-protein ligases, defined by a domain homologous to the E6-AP carboxyl terminus (hect domain).

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.8M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Click on the image to see a larger version.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Jentsch S. The ubiquitin-conjugation system. Annu Rev Genet. 1992;26:179–207. [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]
  • Huibregtse JM, Scheffner M, Howley PM. Cloning and expression of the cDNA for E6-AP, a protein that mediates the interaction of the human papillomavirus E6 oncoprotein with p53. Mol Cell Biol. 1993 Feb;13(2):775–784. [PMC free article] [PubMed]
  • Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell. 1993 Nov 5;75(3):495–505. [PubMed]
  • Werness BA, Levine AJ, Howley PM. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science. 1990 Apr 6;248(4951):76–79. [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]
  • Howley PM, Scheffner M, Huibregtse J, Münger K. Oncoproteins encoded by the cancer-associated human papillomaviruses target the products of the retinoblastoma and p53 tumor suppressor genes. Cold Spring Harb Symp Quant Biol. 1991;56:149–155. [PubMed]
  • Scheffner M, Romanczuk H, Münger K, Huibregtse JM, Mietz JA, Howley PM. Functions of human papillomavirus proteins. Curr Top Microbiol Immunol. 1994;186:83–99. [PubMed]
  • Huibregtse JM, Scheffner M, Howley PM. A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus types 16 or 18. EMBO J. 1991 Dec;10(13):4129–4135. [PMC free article] [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]
  • Huibregtse JM, Scheffner M, Howley PM. Localization of the E6-AP regions that direct human papillomavirus E6 binding, association with p53, and ubiquitination of associated proteins. Mol Cell Biol. 1993 Aug;13(8):4918–4927. [PMC free article] [PubMed]
  • Müller D, Rehbein M, Baumeister H, Richter D. Molecular characterization of a novel rat protein structurally related to poly(A) binding proteins and the 70K protein of the U1 small nuclear ribonucleoprotein particle (snRNP) Nucleic Acids Res. 1992 Apr 11;20(7):1471–1475. [PMC free article] [PubMed]
  • Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990 Oct 5;215(3):403–410. [PubMed]
  • Mansfield E, Hersperger E, Biggs J, Shearn A. Genetic and molecular analysis of hyperplastic discs, a gene whose product is required for regulation of cell proliferation in Drosophila melanogaster imaginal discs and germ cells. Dev Biol. 1994 Oct;165(2):507–526. [PubMed]
  • Martin P, Martin A, Shearn A. Studies of l(3)c43hs1 a polyphasic, temperature-sensitive mutant of Drosophila melanogaster with a variety of imaginal disc defects. Dev Biol. 1977 Feb;55(2):213–232. [PubMed]
  • Kumar S, Tomooka Y, Noda M. Identification of a set of genes with developmentally down-regulated expression in the mouse brain. Biochem Biophys Res Commun. 1992 Jun 30;185(3):1155–1161. [PubMed]
  • Gu J, Ren K, Dubner R, Iadarola MJ. Cloning of a DNA binding protein that is a tyrosine kinase substrate and recognizes an upstream initiator-like sequence in the promoter of the preprodynorphin gene. Brain Res Mol Brain Res. 1994 Jul;24(1-4):77–88. [PubMed]
  • Goebl MG, Goetsch L, Byers B. The Ubc3 (Cdc34) ubiquitin-conjugating enzyme is ubiquitinated and phosphorylated in vivo. Mol Cell Biol. 1994 May;14(5):3022–3029. [PMC free article] [PubMed]
  • Scheffner M, Huibregtse JM, Howley PM. Identification of a human ubiquitin-conjugating enzyme that mediates the E6-AP-dependent ubiquitination of p53. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8797–8801. [PMC free article] [PubMed]
  • Girod PA, Carpenter TB, van Nocker S, Sullivan ML, Vierstra RD. Homologs of the essential ubiquitin conjugating enzymes UBC1, 4, and 5 in yeast are encoded by a multigene family in Arabidopsis thaliana. Plant J. 1993 Apr;3(4):545–552. [PubMed]
  • Treier M, Seufert W, Jentsch S. Drosophila UbcD1 encodes a highly conserved ubiquitin-conjugating enzyme involved in selective protein degradation. EMBO J. 1992 Jan;11(1):367–372. [PMC free article] [PubMed]
  • Zhen M, Heinlein R, Jones D, Jentsch S, Candido EP. The ubc-2 gene of Caenorhabditis elegans encodes a ubiquitin-conjugating enzyme involved in selective protein degradation. Mol Cell Biol. 1993 Mar;13(3):1371–1377. [PMC free article] [PubMed]
  • Seufert W, Jentsch S. Ubiquitin-conjugating enzymes UBC4 and UBC5 mediate selective degradation of short-lived and abnormal proteins. EMBO J. 1990 Feb;9(2):543–550. [PMC free article] [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...