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

Domenico Raimondo, Alejandro Giorgetti, Francesca Bernassola, Gerry Melino, Anna Tramontano

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1620-1627
Number of pages8
JournalBiochemical Pharmacology
Issue number11
Publication statusPublished - Dec 1 2008


  • E3 ubiquitin ligases
  • HECT domain
  • UbcH7

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry


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