ELM Details - LIG

LIG_MDM2

Functional site class:	MDM2 ligand
Functional site description:	p53 derived pattern that confers binding to the N-terminal p53 binding domain of MDM2
ELM(s):	LIG_MDM2
LIG_MDM2 description:	An amphipatic helix found in p53 family members that confers binding to the N-term. p53 binding domain of MDM2
Pattern:	F...W..[LIV]
Present in taxon(s):	Metazoa
Not represented in taxon(s):

See instances for LIG_MDM2

Abstract

MDM2 is an E3 ubiquitin ligase that recognizes the N-terminal transactivating domain (TAD) of the p53 family members p53 (PMID:7686617), p63 (PMID:11445003) and p73 (PMID:10207051), by the N-terminal region that is involved in the transactivating (TAD) ability of p53. The region in p53 that interacts with MDM2, has also been shown to interact with the TAFII31 (TATA-binding assosiated factor 31) which stimulates transcription of genes that control cell growth. PMID:10611293 showed that MDM2 discriminates between TAFII31 binding proteins, and recognizes p53 and not the TAFII31 binding protin VP16. This suggests a slightly different mechanism which the two different proteins, MDM2 and TAFII31, recognizes p53. In both cases an amphipatic helix in the N-terminal region of p53 (PMID:10611293, PMID:9271577) has been shown to mediate the interactions.

The interaction between p53 and TAFII31 has been suggested to be mediated by an Fxxphiphi motif (phi = hydrophobic), and is found in several TAFII31 interacting proteins including; BRCA-1 (PMID:8751436) and NFAT1 (PMID:10821850). The structure of a p53 peptide (containing the Fxxphiphi motif) bound to MDM2 (PMID:8875929, PDB:1YCR), shows that in addition to the Fxxphiphi motif, an additional leucine C-terminally to the of the Fxxphiphi motif is also involved in the interaction. This suggests that the Fxxphiphi motif is masked from recognition by TAFII31. The interaction of p53 with MDM2 leads to ubquitinylation and susequent degradation of p53.

Selected references

Kadakia M, Slader C, Berberich SJ

Regulation of p63 function by Mdm2 and MdmX.

DNA Cell Biol 2001 Jun;20(6) : 321-30.

PMID: 11445003

Kussie PH, Gorina S, Marechal V, Elenbaas B, Moreau J, Levine AJ, Pavletich NP

Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain.

Science 1996 Nov 8;274(5289) : 948-53.

PMID: 8875929

Uesugi M, Verdine GL

The alpha-helical FXXPhiPhi motif in p53: TAF interaction and discrimination by MDM2.

Proc Natl Acad Sci U S A 1999 Dec 21;96(26) : 14801-6.

PMID: 10611293

Zeng X, Chen L, Jost CA, Maya R, Keller D, Wang X, Kaelin WG Jr, Oren M, Chen J, Lu H

MDM2 suppresses p73 function without promoting p73 degradation.

Mol Cell Biol 1999 May;19(5) : 3257-66.

PMID: 10207051

This ELM has been assigned the following Gene Ontology (GO) terms for biological process, cellular component and molecular function.

Biological Process

  cell proliferation

GO:0008283

Cellular Component

  cytosol

GO:0005829

  nucleus

GO:0005634

Molecular Function

  protein degradation tagging activity

GO:0000211

Instances for LIG_MDM2

Sequence	Position	Subsequence (Click for evidence information)	PDB	Gene Name	Protein Description	Organism
P53_HUMAN	19-26	LSQETFSDLWKLLPENNVL	1YCR	Name=TP53; Synonyms=P53;	Cellular tumor antigen p53 (Tumor suppressor p53) (Phosphoprotein p53) (Antigen NY-CO-13).	Homo sapiens (Human).
P73_HUMAN	15-22	DGGTTFEHLWSSLEPDSTY	-	Name=TP73; Synonyms=P73;	Tumor protein p73 (p53-like transcription factor) (p53-related protein).	Homo sapiens (Human).
P63_HUMAN	55-62	LSPEVFQHIWDFLEQPICS	-	Name=TP63; Synonyms=KET, P63, P73H, P73L, TP73L;	Tumor protein 63 (p63) (Transformation-related protein 63) (TP63) (Tumor protein p73-like) (p73L) (p51) (p40) (Keratinocyte transcription factor KET) (Chronic ulcerative stomatitis protein) (CUSP).	Homo sapiens (Human).