Structure of a Ubiquitin-loaded HECT Ligase Reveals the Molecular Basis for Catalytic Priming

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2013 May 7

PMID 23644597

Citations 106

Authors

Elena Maspero

Eleonora Valentini

Sara Mari

Valentina Cecatiello

Paolo Soffientini

Sebastiano Pasqualato

Simona Polo

Affiliations

Soon will be listed here.

Abstract

Homologous to E6-AP C terminus (HECT) E3 ligases recognize and directly catalyze ligation of ubiquitin (Ub) to their substrates. Molecular details of this process remain unknown. We report the first structure, to our knowledge, of a Ub-loaded E3, the human neural precursor cell-expressed developmentally downregulated protein 4 (Nedd4). The HECT(Nedd4)~Ub transitory intermediate provides a structural basis for the proposed sequential addition mechanism. The donor Ub, transferred from the E2, is bound to the Nedd4 C lobe with its C-terminal tail locked in an extended conformation, primed for catalysis. We provide evidence that the Nedd4-family members are Lys63-specific enzymes whose catalysis is mediated by an essential C-terminal acidic residue.

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