Insights into the structural basis of the GADD45beta-mediated inactivation of the JNK kinase, MKK7/JNKK2.

Insights into the structural basis of the GADD45beta-mediated inactivation of the JNK kinase, MKK7/JNKK2. Research Abstract Details 

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Insights into the structural basis of the GADD45beta-mediated inactivation of the JNK kinase, MKK7/JNKK2. Abstract Text:

Salvatore Papa,Simona M Monti,Rosa Maria Vitale,Concetta Bubici,Shanthi Jayawardena,Kellean Alvarez,Enrico De Smaele,Nina Dathan,Carlo Pedone,Menotti Ruvo,Guido Franzoso,

NF-kappaB/Rel factors control programmed cell death (PCD), and this control is crucial to oncogenesis, cancer chemoresistance, and antagonism of tumor necrosis factor (TNF) alpha-induced killing. With TNFalpha, NF-kappaB-mediated protection involves suppression of the c-Jun-N-terminal kinase (JNK) cascade, and we have identified Gadd45beta, a member of the Gadd45 family, as a pivotal effector of this activity of NF-kappaB. Inhibition of TNFalpha-induced JNK signaling by Gadd45beta depends on direct targeting of the JNK kinase, MKK7/JNKK2. The mechanism by which Gadd45beta blunts MKK7, however, is unknown. Here we show that Gadd45beta is a structured protein with a predicted four-stranded beta-sheet core, five alpha-helices, and two acidic loops. Association of Gadd45beta with MKK7 involves a network of interactions mediated by its putative helices alpha3 and alpha4 and loops 1 and 2. Whereas alpha3 appears to primarily mediate docking to MKK7, loop 1 and alpha4-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 Gadd45beta-mediated blockade of MKK7, and ultimately, TNFalpha-induced PCD. They also have important implications for treatment of widespread diseases.

Insights into the structural basis of the GADD45beta-mediated inactivation of the JNK kinase, MKK7/JNKK2. Publishing Authors By Initials

S Papa,SM Monti,RM Vitale,C Bubici,S Jayawardena,K Alvarez,E De Smaele,N Dathan,C Pedone,M Ruvo,G Franzoso,

For similar peptides: intercellular signaling peptides and proteins: cytokines: monokines: tumor necrosis factor-alpha research abstracts see: peptides: intercellular signaling peptides and proteins: cytokines: monokines: tumor necrosis factor-alpha research

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Insights into the structural basis of the GADD45beta-mediated inactivation of the JNK kinase, MKK7/JNKK2. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The Journal of biological chemistry

VOLUME: 282

Page Numbers: 19029-41

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 7

MONTH: 05

YEAR: 2007

Insights into the structural basis of the GADD45beta-mediated inactivation of the JNK kinase, MKK7/JNKK2. Information

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LANGUAGE: eng

NlmUniqueID: 2985121

Insights into the structural basis of the GADD45beta-mediated inactivation of the JNK kinase, MKK7/JNKK2. Keywords Mesh Terms:

KEYWORDS: Tumor Necrosis Factor-alpha

MESH TERMS: pharmacology

Chemical & Substance for Abstract: Insights into the structural basis of the GADD45beta-mediated inactivation of the JNK kinase, MKK7/JNKK2. Information

Substance Name: MAP2K7 protein, human

Registry Number: EC 2.7.1.-

Grant and Affiliation Information for Insights into the structural basis of the GADD45beta-mediated inactivation of the JNK kinase, MKK7/JNKK2.

AFFILIATION: The Ben May Institute for Cancer Research, University of Chicago, Chicago, Illinois 60637, USA.

Country: United States

AGENCY: United States NCI

GRANT: R01 CA84040

ACRONYM: CA

MEDLINETA: J Biol Chem

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