Structural basis for dimerization quality control

Elijah L. Mena, Predrag Jevtić, Basil J. Greber, Christine L. Gee, Brandon G. Lew, David Akopian, Eva Nogales, John Kuriyan and Michael Rape ()
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Elijah L. Mena: University of California at Berkeley
Predrag Jevtić: University of California at Berkeley
Basil J. Greber: University of California at Berkeley
Christine L. Gee: University of California at Berkeley
Brandon G. Lew: University of California at Berkeley
David Akopian: University of California at Berkeley
Eva Nogales: University of California at Berkeley
John Kuriyan: University of California at Berkeley
Michael Rape: University of California at Berkeley

Nature, 2020, vol. 586, issue 7829, 452-456

Abstract: Abstract Most quality control pathways target misfolded proteins to prevent toxic aggregation and neurodegeneration1. Dimerization quality control further improves proteostasis by eliminating complexes of aberrant composition2, but how it detects incorrect subunits remains unknown. Here we provide structural insight into target selection by SCF–FBXL17, a dimerization-quality-control E3 ligase that ubiquitylates and helps to degrade inactive heterodimers of BTB proteins while sparing functional homodimers. We find that SCF–FBXL17 disrupts aberrant BTB dimers that fail to stabilize an intermolecular β-sheet around a highly divergent β-strand of the BTB domain. Complex dissociation allows SCF–FBXL17 to wrap around a single BTB domain, resulting in robust ubiquitylation. SCF–FBXL17 therefore probes both shape and complementarity of BTB domains, a mechanism that is well suited to establish quality control of complex composition for recurrent interaction modules.

Date: 2020
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DOI: 10.1038/s41586-020-2636-7

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