TY - JOUR
T1 - Crystal Structure of the Ubiquitin Binding Domains of Rabex-5 Reveals Two Modes of Interaction with Ubiquitin
AU - Penengo, Lorenza
AU - Mapelli, Marina
AU - Murachelli, Andrea G.
AU - Confalonieri, Stefano
AU - Magri, Laura
AU - Musacchio, Andrea
AU - Di Fiore, Pier Paolo
AU - Polo, Simona
AU - Schneider, Thomas R.
N1 - Funding Information:
We thank L. Hicke and S. Giordano for reagents; E. Cavallaro, V. Cecatiello, and M. Garre for technical assistance; A. Mattevi for providing X-ray facilities; C. Tarricone and R. Steiner for help in data collection; the staff of beamlines ID29 and BM14 at ESRF; and the Monoclonal Service at IFOM. This work was supported by grants from Associazione Italiana per la Ricerca sul Cancro (S.P., P.P.D.F., T.R.S., A.M.); Association for International Cancer Research (S.P.); European Community (VI Framework), Ministero della Salute, MIUR, Fondazione Monzino (P.P.D.F.).
PY - 2006/3/24
Y1 - 2006/3/24
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/33646036373
U2 - 10.1016/j.cell.2006.02.020
DO - 10.1016/j.cell.2006.02.020
M3 - Article
SN - 0092-8674
VL - 124
SP - 1183
EP - 1195
JO - Cell
JF - Cell
IS - 6
ER -