TY - JOUR
T1 - Structure of a ubiquitin-loaded HECT ligase reveals the molecular basis for catalytic priming
AU - Maspero, Elena
AU - Valentini, Eleonora
AU - Mari, Sara
AU - Cecatiello, Valentina
AU - Soffientini, Paolo
AU - Pasqualato, Sebastiano
AU - Polo, Simona
PY - 2013/6
Y1 - 2013/6
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=84878900697&partnerID=8YFLogxK
U2 - 10.1038/nsmb.2566
DO - 10.1038/nsmb.2566
M3 - Article
C2 - 23644597
AN - SCOPUS:84878900697
VL - 20
SP - 696
EP - 701
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
SN - 1545-9993
IS - 6
ER -