Crystal Structure of the Ubiquitin Binding Domains of Rabex-5 Reveals Two Modes of Interaction with Ubiquitin

Lorenza Penengo, Marina Mapelli, Andrea G. Murachelli, Stefano Confalonieri, Laura Magri, Andrea Musacchio, Pier Paolo Di Fiore, Simona Polo, Thomas R. Schneider

Research output: Contribution to journalArticle


The interaction between ubiquitinated proteins and intracellular proteins harboring ubiquitin binding domains (UBDs) is critical to a multitude of cellular processes. Here, we report that Rabex-5, a guanine nucleotide exchange factor for Rab5, binds to Ub through two independent UBDs. These UBDs determine a number of properties of Rabex-5, including its coupled monoubiquitination and interaction in vivo with ubiquitinated EGFRs. Structural and biochemical characterization of the UBDs of Rabex-5 revealed that one of them (MIU, motif interacting with ubiquitin) binds to Ub with modes superimposable to those of the UIM (ubiquitin-interacting motif):Ub interaction, although in the opposite orientation. The other UBD, RUZ (Rabex-5 ubiquitin binding zinc finger) binds to a surface of Ub centered on Asp58Ub and distinct from the "canonical" Ile44Ub-based surface. The two binding surfaces allow Ub to interact simultaneously with different UBDs, thus opening new perspectives in Ub-mediated signaling.

Original languageEnglish
Pages (from-to)1183-1195
Number of pages13
Issue number6
Publication statusPublished - Mar 24 2006


ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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