Biol Chem. 2018 Jan 26;399(2):127-145. doi: 10.1515/hsz-2017-0184.
Structural mechanisms of HECT-type ubiquitin ligases.
Lorenz S1.
Abstract
Ubiquitin ligases (E3
enzymes) transfer ubiquitin from ubiquitin-conjugating (E2) enzymes to
target proteins. By determining the selection of target proteins,
modification sites on those target proteins, and the types of ubiquitin
modifications that are formed, E3
enzymes are key specificity factors in ubiquitin signaling. Here, I
summarize our knowledge of the structural mechanisms in the HECT E3 subfamily, many members of which play important roles in human disease. I discuss interactions of the conserved HECT
domain with E2 enzymes, ubiquitin and target proteins, as well as
macromolecular interactions with regulatory functions. While we
understand individual steps in the catalytic cycle of HECT E3
enzymes on a structural level, this review also highlights key aspects
that have yet to be elucidated. For instance, it remains unclear how
diverse target proteins are presented to the catalytic center and how
certain HECT E3
enzymes achieve specificity in ubiquitin linkage formation. The
structural and functional properties of the N-terminal regions of HECT E3
enzymes that likely act as signaling hubs are also largely unknown.
Structural insights into these aspects may open up routes for a
therapeutic intervention with specific HECT E3 functions in distinct pathophysiological settings.
KEYWORDS:E3 enzyme; X-ray crystallography; enzyme mechanism; enzyme regulation; posttranslational modification
PMID: 29016349 DOI: 10.1515/hsz-2017-0184
https://www.cell.com/molecular-cell/pdf/S1097-2765(17)30230-7.pdf
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