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Structure of the APPL1 BAR‐PH domain and characterization of its interaction with Rab5
Author(s) -
Zhu Guangyu,
Chen Jia,
Liu Jay,
Brunzelle Joseph S,
Huang Bo,
Wakeham Nancy,
Terzyan Simon,
Li Xuemei,
Rao Zihe,
Li Guangpu,
Zhang Xuejun C
Publication year - 2007
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601771
Subject(s) - gtpase , biology , rab , binding site , linker , crystallography , signal transducing adaptor protein , biophysics , plasma protein binding , dimer , guanine nucleotide exchange factor , binding domain , helix (gastropod) , biochemistry , receptor , chemistry , computer science , operating system , ecology , organic chemistry , snail
APPL1 is an effector of the small GTPase Rab5. Together, they mediate a signal transduction pathway initiated by ligand binding to cell surface receptors. Interaction with Rab5 is confined to the amino (N)‐terminal region of APPL1. We report the crystal structures of human APPL1 N‐terminal BAR‐PH domain motif. The BAR and PH domains, together with a novel linker helix, form an integrated, crescent‐shaped, symmetrical dimer. This BAR–PH interaction is likely conserved in the class of BAR‐PH containing proteins. Biochemical analyses indicate two independent Rab‐binding sites located at the opposite ends of the dimer, where the PH domain directly interacts with Rab5 and Rab21. Besides structurally supporting the PH domain, the BAR domain also contributes to Rab binding through a small surface region in the vicinity of the PH domain. In stark contrast to the helix‐dominated, Rab‐binding domains previously reported, APPL1 PH domain employs β‐strands to interact with Rab5. On the Rab5 side, both switch regions are involved in the interaction. Thus we identified a new binding mode between PH domains and small GTPases.