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 a Stjepan ULDRIJAN

Základní údaje

Originální název

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

Autoři

DOLEŽELOVÁ, Pavlína (203 Česká republika, domácí), Kateřina CETKOVSKÁ (203 Česká republika, domácí), Karen H. VOUSDEN (826 Velká Británie a Severní Irsko) a Stjepan ULDRIJAN (203 Česká republika, garant, domácí)

Vydání

Cell Cycle, 2012, 1538-4101

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

Genetika a molekulární biologie

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 5.321

Kód RIV

RIV/00216224:14110/12:00057309

Organizační jednotka

Lékařská fakulta

DOI

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

UT WoS

000300989700024

Klíčová slova anglicky

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

Příznaky

Mezinárodní význam

Změněno: 16. 4. 2013 17:31, Ing. Mgr. Věra Pospíšilíková

Anotace

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.

Návaznosti

GA301/09/1324, projekt VaV

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

Investor: Grantová agentura ČR, Funkce centrální domény onkoproteinu Mdm2 a jejich nových vazebných partnerů při regulaci nádorového supresoru p53

Citovat

DOLEŽELOVÁ, Pavlína, Kateřina CETKOVSKÁ, Karen H. VOUSDEN a 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, roč. 11, č. 5, s. 953-962. ISSN 1538-4101. Dostupné z: 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 a 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, roč.~11, č.~5, s.~953-962. ISSN~1538-4101. Dostupné z: https://dx.doi.org/10.4161/cc.11.5.19445.

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