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    Home > Biochemistry News > Biotechnology News > Advances in the study of the synthesis mechanism of linear ubitin chain assembly complex (LUBAC).

    Advances in the study of the synthesis mechanism of linear ubitin chain assembly complex (LUBAC).

    • Last Update: 2020-08-22
    • Source: Internet
    • Author: User
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    The ubichemical modification of protein is a kind of protein post-translation modification with many effects, which is closely related to many physiological processes and diseases.
    linear ubigenization is a new type of ubitin modification, widely involved in inflammation, anti-invasion pathogens of selective autophagy and innate immune-related signaling pathologies.
    Linear Ubiquitin Chain Assembly Complex (LUBAC) is the only mesolineive Ubiquitin chain synthesis of E3 Ubiquitin lyse, consisting of catalytic sub-base HOIP and two regulated sub-base SHARPIN, HOIL-1L.
    , the loss of function of any sub-base in LUBAC can cause inflammation, immunodeficiency and even embryonic death in mouse models or humans.
    studies have shown that HOIP alone is in a low-activity state, and there is self-inhibition between its own UBA domain and catalytic core region.
    the combination of HOIL-1L or SHARPIN can activate HOIP, effectively catalyzing the synthesis of linear ubigen chains, but the structural basis of HOIP self-inhibition and the molecular process of SHARPIN and HOIL-1L activating HOIP are still unknown.
    Recently, Pan Lifeng of the National Key Laboratory of Life Organic Chemistry of the Shanghai Institute of Organic Chemistry of the Chinese Academy of Sciences successfully analyzed the crystal structure of the composite compound of the HOIP UBA domain combined with the SHARPIN UBL domain, and found that SHARPIN and HOIL-1L can be combined at the same time with two distinct bits on the UBA domain of HOIP, which can activate the enzyme activity of HOP individually and in synergy. The biochemical and enzymatic experimental studies of
    systems reveal in detail the activation mechanism of HOIP: the combination of SHARPIN or HOIL-1L, which changes the relative orientation of the UBA structural domain and catalytic core region, thus relieving self-inhibition and promoting substrates into the catalytic core and accelerating linear ubitin chain synthesis.
    work also clearly addresses a fundamental issue that has been hotly debated in previous studies: which domain of HOIP directly combines SHARPIN? Using protein complex structure and biochemical experiments, researchers at Shanghai Organic Institute confirmed that ITI's UBA domain, rather than the NZF2 domain, binds to SHARPIN.
    the synergy of SHARPIN and HOIL-1L HOIP also explains the three different combinations of LUBAC complexes present in cells, as well as the corresponding different enzyme activity.
    the study was published online in Cell Reports (2017, 21, 1-10) under the title Structural Insights into SHARPIN-Mediated Activation of HOIP for The Linear Ubiquitin Chain Assembly.
    the research work has been the Chinese Academy of Sciences strategic pilot science and technology special (class B), the National Key Laboratory of Organic Chemistry for Life, the National Natural Science Foundation of China, the Ministry of Science and Technology, the Central Group Department of the Youth Thousand Program and the Shanghai Science and Technology Commission related funding.
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