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TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin.

Identifieur interne : 001B10 ( Main/Exploration ); précédent : 001B09; suivant : 001B11

TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin.

Auteurs : M C Lorenz [États-Unis] ; J. Heitman

Source :

RBID : pubmed:7499212

Descripteurs français

English descriptors

Abstract

The antifungal, immunosuppressive compound rapamycin arrests the cell cycle in G1 in both yeast cells and T-lymphocytes. Previous genetic studies in yeast identified mutations in three genes, FPR1 (FKBP12), TOR1, and TOR2, which confer rapamycin resistance, and genetic findings implicated the TOR proteins as direct targets of FKBP12-rapamycin. Consistent with this model, we find that modulating TOR1 and TOR2 expression alters rapamycin sensitivity. We describe several TOR2 mutations that confer rapamycin resistance. These mutations prevent FKBP12-rapamycin binding to TOR2, as assayed with the two-hybrid system. We find that TOR1 and the mammalian TOR homologue (mTOR) also bind FKBP12-rapamycin, and mutations corresponding to those in TOR2 similarly block FKBP12-rapamycin binding. We demonstrate that FKBP12 prolyl isomerase activity is not required for FKBP12-rapamycin binding to TOR and that a composite protein-drug surface contacts the TOR proteins. These studies confirm that the TOR proteins are direct targets of FKBP12-rapamycin, reveal that drug-resistant mutations prevent this association, and define structural features of these complexes.

DOI: 10.1074/jbc.270.46.27531
PubMed: 7499212


Affiliations:


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Le document en format XML

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<term>Antifungal Agents (pharmacology)</term>
<term>Base Sequence (MeSH)</term>
<term>Carrier Proteins (metabolism)</term>
<term>Cell Cycle Proteins (MeSH)</term>
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<term>Saccharomyces cerevisiae (genetics)</term>
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<term>Antifongiques (pharmacologie)</term>
<term>Cinétique (MeSH)</term>
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<term>Gènes fongiques (MeSH)</term>
<term>Liaison aux protéines (MeSH)</term>
<term>Phosphatidylinositol 3-kinases (MeSH)</term>
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<term>Polyènes (pharmacologie)</term>
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<term>Résistance microbienne aux médicaments (génétique)</term>
<term>Saccharomyces cerevisiae (effets des médicaments et des substances chimiques)</term>
<term>Saccharomyces cerevisiae (génétique)</term>
<term>Saccharomyces cerevisiae (métabolisme)</term>
<term>Sirolimus (MeSH)</term>
<term>Séquence nucléotidique (MeSH)</term>
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<term>Antifungal Agents</term>
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<term>Recombinant Proteins</term>
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<term>Gènes fongiques</term>
<term>Liaison aux protéines</term>
<term>Phosphatidylinositol 3-kinases</term>
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<term>Protéines de liaison au tacrolimus</term>
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<div type="abstract" xml:lang="en">The antifungal, immunosuppressive compound rapamycin arrests the cell cycle in G1 in both yeast cells and T-lymphocytes. Previous genetic studies in yeast identified mutations in three genes, FPR1 (FKBP12), TOR1, and TOR2, which confer rapamycin resistance, and genetic findings implicated the TOR proteins as direct targets of FKBP12-rapamycin. Consistent with this model, we find that modulating TOR1 and TOR2 expression alters rapamycin sensitivity. We describe several TOR2 mutations that confer rapamycin resistance. These mutations prevent FKBP12-rapamycin binding to TOR2, as assayed with the two-hybrid system. We find that TOR1 and the mammalian TOR homologue (mTOR) also bind FKBP12-rapamycin, and mutations corresponding to those in TOR2 similarly block FKBP12-rapamycin binding. We demonstrate that FKBP12 prolyl isomerase activity is not required for FKBP12-rapamycin binding to TOR and that a composite protein-drug surface contacts the TOR proteins. These studies confirm that the TOR proteins are direct targets of FKBP12-rapamycin, reveal that drug-resistant mutations prevent this association, and define structural features of these complexes.</div>
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   |étape=   Exploration
   |type=    RBID
   |clé=     pubmed:7499212
   |texte=   TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin.
}}

Pour générer des pages wiki

HfdIndexSelect -h $EXPLOR_AREA/Data/Main/Exploration/RBID.i   -Sk "pubmed:7499212" \
       | HfdSelect -Kh $EXPLOR_AREA/Data/Main/Exploration/biblio.hfd   \
       | NlmPubMed2Wicri -a RapamycinFungusV1 

Wicri

This area was generated with Dilib version V0.6.38.
Data generation: Thu Nov 19 21:55:41 2020. Site generation: Thu Nov 19 22:00:39 2020