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Abstract:
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 Asp58(Ub) and distinct from the
"canonical" Ile44(Ub)-based surface. The two binding surfaces allow Ub
to interact simultaneously with different UBDs, thus opening new
perspectives in Ub-mediated signaling.