Imperial College London
Alternate

DrConcettaBubici

Faculty of Medicine, Faculty of Medicine Centre

Honorary Clinical Lecturer
 
 
 
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Contact

 

+44 (0)20 3313 8432c.bubici

 
 
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Location

 

10.N6Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Papa:2007:10.1074/jbc.M703112200,
author = {Papa, S and Monti, SM and Vitale, RM and Bubici, C and Jayawardena, S and Alvarez, K and De, Smaele E and Dathan, N and Pedone, C and Ruvo, M and Franzoso, G},
doi = {10.1074/jbc.M703112200},
journal = {J Chem Biol},
pages = {19029--19041},
title = {Insights into the structural basis of the Gadd45ß mediated inactivation of the JNK kinase, MKK7},
url = {http://dx.doi.org/10.1074/jbc.M703112200},
volume = {282},
year = {2007}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - NF-B/Rel factors control programmed cell death (PCD), and this control is crucial to oncogenesis, cancer chemoresistance, and antagonism of tumor necrosis factor (TNF) -induced killing. With TNF, NF-B-mediated protection involves suppression of the c-Jun-N-terminal kinase (JNK) cascade, and we have identified Gadd45, a member of the Gadd45 family, as a pivotal effector of this activity of NF-B. Inhibition of TNF-induced JNK signaling by Gadd45 depends on direct targeting of the JNK kinase, MKK7/JNKK2. The mechanism by which Gadd45 blunts MKK7, however, is unknown. Here we show that Gadd45 is a structured protein with a predicted four-stranded -sheet core, five -helices, and two acidic loops. Association of Gadd45 with MKK7 involves a network of interactions mediated by its putative helices 3 and 4 and loops 1 and 2. Whereas 3 appears to primarily mediate docking to MKK7, loop 1 and 4-loop 2 seemingly afford kinase inactivation by engaging the ATP-binding site and causing conformational changes that impede catalytic function. These data provide a basis for Gadd45-mediated blockade of MKK7, and ultimately, TNF-induced PCD. They also have important implications for treatment of widespread diseases.
AU  - Papa,S
AU  - Monti,SM
AU  - Vitale,RM
AU  - Bubici,C
AU  - Jayawardena,S
AU  - Alvarez,K
AU  - De,Smaele E
AU  - Dathan,N
AU  - Pedone,C
AU  - Ruvo,M
AU  - Franzoso,G
DO  - 10.1074/jbc.M703112200
EP  - 19041
PY  - 2007///
SP  - 19029
TI  - Insights into the structural basis of the Gadd45ß mediated inactivation of the JNK kinase, MKK7
T2  - J Chem Biol
UR  - http://dx.doi.org/10.1074/jbc.M703112200
VL  - 282
ER  -
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