Direct Role for Proliferating Cell Nuclear Antigen in Substrate Recognition by the E3 Ubiquitin Ligase CRL4Cdt2.
Author: Havens, Courtney G.; Shobnam, Nadia; Guarino Almeida, Estrella; Centore, Richard C.; Zou, Lee; Kearsey, Stephen E.; Walter, Johannes C.
Abstract: The E3 ubiquitin ligase Cullin-ring ligase 4-Cdt2 (CRL4Cdt2)
is emerging as an important cell cycle regulator that targets
numerous proteins for destruction in S phase and after DNA
damage, including Cdt1, p21, and Set8. CRL4Cdt2 substrates
contain a “PIP degron,” which consists of a canonical proliferating
cell nuclear antigen (PCNA) interaction motif (PIP box)
and an adjacent basic amino acid. Substrates use their PIP box to
form a binary complex with PCNA on chromatin and the basic
residue to recruit CRL4Cdt2 for substrate ubiquitylation. Using
Xenopus egg extracts, we identify an acidic residue inPCNAthat
is essential to support destruction of all CRL4Cdt2 substrates.
This PCNA residue, which adjoins the basic amino acid of the
bound PIP degron, is dispensable for substrate binding toPCNA
but essential for CRL4Cdt2 recruitment to chromatin. Our data
show that the interaction of CRL4Cdt2 with substrates requires
molecular determinants not only in the substrate degron but
also on PCNA. The results illustrate a potentially general mechanism
by which E3 ligases can couple ubiquitylation to the formation
of protein-protein interactions.
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