Modelling and molecular dynamics of the interaction between the E3 ubiquitin ligase Itch and the E2 UbcH7.

Abstract:

:Itch, a member of the E6AP carboxy terminus (HECT) domain-containing family of ubiquitin E3 ligases, acts in concert with the ubiquitin activating enzyme (E1) and the ubiquitin conjugating enzyme (E2) to catalyze ubiquitylation of protein targets. This sub-family of E3s shares a 350 residue C-terminal HECT domain having a strictly conserved catalytic Cys, and recruiting its cognate ubiquitin-loaded E2. HECT domains possess intrinsic enzymatic activity, by accepting ubiquitin from an E2, forming a ubiquitin thiolester intermediate, and directly catalyzing ubiquitylation of the target protein. Several hypotheses have been proposed for the biochemical mechanism underlying the structural relationship of the HECT-E2 association and subsequent ubiquitin transfer. Nonetheless, a detailed characterization of the process is still missing. In this work, we have used molecular dynamic simulations, free energy calculations, protein modelling techniques and normal modes analysis to get a deeper characterization of the static and dynamical properties of this interaction mechanism. We hypothesize a correlated slow-frequency motion that involves two different hinge regions of the HECT domain. The identification of the amino acid residues responsible for the HECT-E2 interaction, and for the dynamical properties of the ubiquitin transfer process, may be of relevant interest for pharmacological and therapeutical purposes.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Raimondo D,Giorgetti A,Bernassola F,Melino G,Tramontano A

doi

10.1016/j.bcp.2008.08.026

subject

Has Abstract

pub_date

2008-12-01 00:00:00

pages

1620-7

issue

11

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(08)00593-5

journal_volume

76

pub_type

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