Structural dynamics of the E6AP/UBE3A-E6-p53 enzyme-substrate complex

Carolin Sailer, Fabian Offensperger, Alexandra Julier, Kai-Michael Kammer, Ryan Walker-Gray, Matthew G. Gold, Martin Scheffner () and Florian Stengel ()
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Carolin Sailer: University of Konstanz
Fabian Offensperger: University of Konstanz
Alexandra Julier: University of Konstanz
Kai-Michael Kammer: University of Konstanz
Ryan Walker-Gray: University College London
Matthew G. Gold: University College London
Martin Scheffner: University of Konstanz
Florian Stengel: University of Konstanz

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract Deregulation of the ubiquitin ligase E6AP is causally linked to the development of human disease, including cervical cancer. In complex with the E6 oncoprotein of human papillomaviruses, E6AP targets the tumor suppressor p53 for degradation, thereby contributing to carcinogenesis. Moreover, E6 acts as a potent activator of E6AP by a yet unknown mechanism. However, structural information explaining how the E6AP-E6-p53 enzyme-substrate complex is assembled, and how E6 stimulates E6AP, is largely missing. Here, we develop and apply different crosslinking mass spectrometry-based approaches to study the E6AP-E6-p53 interplay. We show that binding of E6 induces conformational rearrangements in E6AP, thereby positioning E6 and p53 in the immediate vicinity of the catalytic center of E6AP. Our data provide structural and functional insights into the dynamics of the full-length E6AP-E6-p53 enzyme-substrate complex, demonstrating how E6 can stimulate the ubiquitin ligase activity of E6AP while facilitating ubiquitin transfer from E6AP onto p53.

Date: 2018
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DOI: 10.1038/s41467-018-06953-0

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