Kinetic analysis of multistep USP7 mechanism shows critical role for target protein in activity View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

Robbert Q. Kim, Paul P. Geurink, Monique P. C. Mulder, Alexander Fish, Reggy Ekkebus, Farid El Oualid, Willem J. van Dijk, Duco van Dalen, Huib Ovaa, Hugo van Ingen, Titia K. Sixma

ABSTRACT

USP7 is a highly abundant deubiquitinating enzyme (DUB), involved in cellular processes including DNA damage response and apoptosis. USP7 has an unusual catalytic mechanism, where the low intrinsic activity of the catalytic domain (CD) increases when the C-terminal Ubl domains (Ubl45) fold onto the CD, allowing binding of the activating C-terminal tail near the catalytic site. Here we delineate how the target protein promotes the activation of USP7. Using NMR analysis and biochemistry we describe the order of activation steps, showing that ubiquitin binding is an instrumental step in USP7 activation. Using chemically synthesised p53-peptides we also demonstrate how the correct ubiquitinated substrate increases catalytic activity. We then used transient reaction kinetic modelling to define how the USP7 multistep mechanism is driven by target recognition. Our data show how this pleiotropic DUB can gain specificity for its cellular targets. More... »

PAGES

231

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-018-08231-5

    DOI

    http://dx.doi.org/10.1038/s41467-018-08231-5

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1111348253

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30651545


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