Mutational analysis of Mdm2 C-terminal tail suggests an
evolutionarily conserved role of its length in Mdm2 activity
toward p53 and indicates structural differences between Mdm2
homodimers and Mdm2/MdmX heterodimers

J 2012

Mutational analysis of Mdm2 C-terminal tail suggests an evolutionarily conserved role of its length in Mdm2 activity toward p53 and indicates structural differences between Mdm2 homodimers and Mdm2/MdmX heterodimers

DOLEŽELOVÁ, Pavlína, Kateřina CETKOVSKÁ, Karen H. VOUSDEN and Stjepan ULDRIJAN

Basic information

Original name

Mutational analysis of Mdm2 C-terminal tail suggests an evolutionarily conserved role of its length in Mdm2 activity toward p53 and indicates structural differences between Mdm2 homodimers and Mdm2/MdmX heterodimers

Authors

DOLEŽELOVÁ, Pavlína (203 Czech Republic, belonging to the institution), Kateřina CETKOVSKÁ (203 Czech Republic, belonging to the institution), Karen H. VOUSDEN (826 United Kingdom of Great Britain and Northern Ireland) and Stjepan ULDRIJAN (203 Czech Republic, guarantor, belonging to the institution)

Edition

Cell Cycle, 2012, 1538-4101

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

Genetics and molecular biology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 5.321

RIV identification code

RIV/00216224:14110/12:00057309

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.4161/cc.11.5.19445

UT WoS

000300989700024

Keywords in English

p53; Mdm2; RING domain; ubiquitylation; ubiquitin ligase; E3

Abstract

V originále

Mdm2 can mediate p53 ubiquitylation and degradation either in the form of the Mdm2 homodimer or Mdm2/MdmX heterodimer. The ubiquitin ligase activity of these complexes resides mainly in their respective RING finger domains and also requires adjacent C-terminal tails. So far, structural studies have failed to show significant differences between Mdm2 RING homodimers and Mdm2/MdmX RING heterodimers. Here, we report that not only the primary amino acid sequence, but also the length of the C-terminal tail of Mdm2 is highly conserved through evolution and plays an important role in Mdm2 activity toward p53. Mdm2 mutants with extended C termini do not ubiquitylate p53 despite being capable of forming Mdm2 homodimers through both RING-acidic domain and RING-RING interactions. All extended mutants also retained the ability to interact with MdmX, and this interaction led to reactivation of their E3 ubiquitin ligase activity. In contrast, only a subset of extended Mdm2 mutants was activated by the interaction with Mdm2 RING domain, suggesting that Mdm2 homodimers and Mdm2/MdmX heterodimers may not be structurally and functionally fully equivalent.

Links

GA301/09/1324, research and development project

Name: Funkce centrální domény onkoproteinu Mdm2 a jejích nových vazebných partnerů při regulaci nádorového supresoru p53

Investor: Czech Science Foundation

Citovat

DOLEŽELOVÁ, Pavlína, Kateřina CETKOVSKÁ, Karen H. VOUSDEN and Stjepan ULDRIJAN. Mutational analysis of Mdm2 C-terminal tail suggests an evolutionarily conserved role of its length in Mdm2 activity toward p53 and indicates structural differences between Mdm2 homodimers and Mdm2/MdmX heterodimers. Cell Cycle. 2012, vol. 11, No 5, p. 953-962. ISSN 1538-4101. Available from: https://dx.doi.org/10.4161/cc.11.5.19445.

@article{976730,
   author = {Doleželová, Pavlína and Cetkovská, Kateřina and Vousden, Karen H. and Uldrijan, Stjepan},
   article_number = {5},
   doi = {http://dx.doi.org/10.4161/cc.11.5.19445},
   keywords = {p53; Mdm2; RING domain; ubiquitylation; ubiquitin ligase; E3},
   language = {eng},
   issn = {1538-4101},
   journal = {Cell Cycle},
   title = {Mutational analysis of Mdm2 C-terminal tail suggests an evolutionarily conserved role of its length in Mdm2 activity toward p53 and indicates structural differences between Mdm2 homodimers and Mdm2/MdmX heterodimers},
   volume = {11},
   year = {2012}
}

TY  - JOUR
ID  - 976730
AU  - Doleželová, Pavlína - Cetkovská, Kateřina - Vousden, Karen H. - Uldrijan, Stjepan
PY  - 2012
TI  - Mutational analysis of Mdm2 C-terminal tail suggests an evolutionarily conserved role of its length in Mdm2 activity toward p53 and indicates structural differences between Mdm2 homodimers and Mdm2/MdmX heterodimers
JF  - Cell Cycle
VL  - 11
IS  - 5
SP  - 953-962
EP  - 953-962
SN  - 15384101
KW  - p53
KW  - Mdm2
KW  - RING domain
KW  - ubiquitylation
KW  - ubiquitin ligase
KW  - E3
N2  - Mdm2 can mediate p53 ubiquitylation and degradation either in the form of the Mdm2 homodimer or Mdm2/MdmX heterodimer. The ubiquitin ligase activity of these complexes resides mainly in their respective RING finger domains and also requires adjacent C-terminal tails. So far, structural studies have failed to show significant differences between Mdm2 RING homodimers and Mdm2/MdmX RING heterodimers. Here, we report that not only the primary amino acid sequence, but also the length of the C-terminal tail of Mdm2 is highly conserved through evolution and plays an important role in Mdm2 activity toward p53. Mdm2 mutants with extended C termini do not ubiquitylate p53 despite being capable of forming Mdm2 homodimers through both RING-acidic domain and RING-RING interactions. All extended mutants also retained the ability to interact with MdmX, and this interaction led to reactivation of their E3 ubiquitin ligase activity. In contrast, only a subset of extended Mdm2 mutants was activated by the interaction with Mdm2 RING domain, suggesting that Mdm2 homodimers and Mdm2/MdmX heterodimers may not be structurally and functionally fully equivalent.
ER  -

DOLEŽELOVÁ, Pavlína, Kateřina CETKOVSKÁ, Karen H. VOUSDEN and Stjepan ULDRIJAN. Mutational analysis of Mdm2 C-terminal tail suggests an evolutionarily conserved role of its length in Mdm2 activity toward p53 and indicates structural differences between Mdm2 homodimers and Mdm2/MdmX heterodimers. \textit{Cell Cycle}. 2012, vol.~11, No~5, p.~953-962. ISSN~1538-4101. Available from: https://dx.doi.org/10.4161/cc.11.5.19445.

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