國家衛生研究院 NHRI:Item 3990099045/2159
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    題名: Heptad repeats regulate protein phosphatase 2A recruitment to I-kappa B kinase gamma/NF-kappa B essential modulator and are targeted by human T-lymphotropic virus type 1 tax
    作者: Hong, S;Wang, LC;Gao, X;Kuo, YL;Liu, BY;Merling, R;Kung, HJ;Shih, HM;Giam, CZ
    貢獻者: Division of Molecular and Genomic Medicine
    摘要: The switching on-and-off of I-kappa B kinase (IKK) and NF-kappa B occurs rapidly after signaling. How activated IKK becomes down-regulated is not well understood. Here we show that following tumor necrosis factor-alpha stimulation, protein phosphatase 2A (PP2A) association with IKK is increased. A heptad repeat in IKK gamma, helix 2 (HLX2), mediates PP2A recruitment. Two other heptad repeats downstream of HLX2, termed coiled-coil region 2 (CCR2) and leucine zipper (LZ), bind HLX2 and negatively regulate HLX2 interaction with PP2A. HTLV-1 transactivator Tax also binds HLX2, and this interaction is enhanced by CCR2 but reduced by LZ. In the presence of Tax, PP2A-IKK gamma binding is greatly strengthened. Interestingly, peptides spanning CCR2 and/or LZ disrupt IKK gamma Tax and IKK gamma-PP2A interactions and potently inhibit NF-kappa B activation by Tax and tumor necrosis factor-alpha. We propose that when IKK is resting, HLX2, CCR2, and LZ form a helical bundle in which HLX2 is sequestered. The HLX2-CCR2-LZ bundle becomes unfolded by signal-induced modifications of IKK gamma or after Tax binding. In this conformation, IKK becomes activated. IKK gamma then recruits PP2A via the exposed HLX2 domain for rapid down-regulation of IKK. Tax-PP2A interaction, however, renders PP2A inactive, thus maintaining Tax-PP2A-IKK in an active state. Finally, CCR2 and LZ possibly inhibit IKK activation by stabilizing the HLX2-CCR2-LZ bundle.
    關鍵詞: Biochemistry & Molecular Biology
    日期: 2007-04-20
    關聯: Journal of Biological Chemistry. 2007 Apr;282(16):12119-12126.
    Link to: http://dx.doi.org/10.1074/jbc.M610392200
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1083-351X&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000245941900054
    Cited Times(Scopus): http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=34249717337
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