Structure of a ubiquitin-loaded HECT ligase reveals the molecular basis for catalytic priming

Elena Maspero, Eleonora Valentini, Sara Mari, Valentina Cecatiello, Paolo Soffientini, Sebastiano Pasqualato, Simona Polo

Research output: Contribution to journalArticle

74 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)696-701
Number of pages6
JournalNature Structural and Molecular Biology
Volume20
Issue number6
DOIs
Publication statusPublished - Jun 2013

Fingerprint

Ligases
Ubiquitin
Catalysis
Ubiquitin-Protein Ligases
Ligation
Tail
Down-Regulation
Enzymes
Proteins

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Structure of a ubiquitin-loaded HECT ligase reveals the molecular basis for catalytic priming. / Maspero, Elena; Valentini, Eleonora; Mari, Sara; Cecatiello, Valentina; Soffientini, Paolo; Pasqualato, Sebastiano; Polo, Simona.

In: Nature Structural and Molecular Biology, Vol. 20, No. 6, 06.2013, p. 696-701.

Research output: Contribution to journalArticle

@article{e69ab52147534b39b125d43d4fb0530f,
title = "Structure of a ubiquitin-loaded HECT ligase reveals the molecular basis for catalytic priming",
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.",
author = "Elena Maspero and Eleonora Valentini and Sara Mari and Valentina Cecatiello and Paolo Soffientini and Sebastiano Pasqualato and Simona Polo",
year = "2013",
month = "6",
doi = "10.1038/nsmb.2566",
language = "English",
volume = "20",
pages = "696--701",
journal = "Nature Structural and Molecular Biology",
issn = "1545-9993",
publisher = "Nature Publishing Group",
number = "6",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=84878900697&partnerID=8YFLogxK

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 -