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Crystal Structure of Rab11 in Complex with Rab11 Family Interacting Protein 2

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Crystal Structure of Rab11 in Complex with Rab11 Family Interacting Protein 2 Structure 14, 1273–1283, August 2006 ª2006 Elsevier Ltd All rights reserved DOI 10.1016/j.str.2006.06.010 Crystal Structure of Rab11 in Complex with Rab11 Family Interacting Protein 2 William N. Jagoe,1 Andrew J. Lindsay,2 restricted to epithelial cells (Goldenring et al., 1993). Randy J. Read,3 Airlie J. McCoy,3 The Rab11 proteins regulate the endosomal recycling Mary W. McCaffrey,2 and Amir R. Khan1,* transport of vesicular cargo containing transferrin recep- 1 School of Biochemistry and Immunology tors (Ullrich et al., 1996; Wilcke et al., 2000; Prekeris et al., Trinity College 2000; Lindsay and McCaffrey, 2002), the chemokine Dublin 2 receptor CXCR2 (Fan et al., 2004), and polymeric IgA Ireland receptors (Wang et al., 2000). More recently, Rab25 has 2 Molecular Cell Biology Laboratory been shown to determine the aggressiveness of breast Department of Biochemistry and ovarian cancers, and its expression has been linked Biosciences Institute to tumorigenesis (Cheng et al., 2004, 2006). University College Cork The biological effects of Rabs are elicited by their GTP Cork bound conformation through interactions with effector Ireland proteins. The structures of Rabs have a common G pro- 3 Department of Haematology tein fold with a central six-stranded (mixed) b sheet University of Cambridge flanked by a helices on both sides. The nucleotide state Cambridge Institute for Medical Research of Rabs affects the local conformation of a pair of highly Wellcome Trust/MRC Building conserved regions termed switch 1 and switch 2 (Vetter Hills Road and Wittinghofer, 2001). The crystal structures of Rab3- Cambridge, CB2 2XY rabphilin, Rab4-rabenosyn5, Rab5-rabaptin5, Rab7-RILP, United Kingdom and Rab22-rabenosyn5 have been determined (Oster- meier and Brunger, 1999; Zhu et al., 2004; Wu et al., 2005a; Eathiraj et al., 2005), and both switch 1 and switch Summary 2 have well-defined electron density in these structures. Switch 1 and/or switch 2 contribute to interactions with The small GTPase Rab11 regulates the recycling of the Rab binding domain (RBD) of effectors, which are endosomes to the plasma membrane via interactions generally a-helical in conformation (Kawasaki et al., with the Rab11 family of interacting proteins (FIPs). 2005). However, the orientation of the helices, the oligo- FIPs contain a highly conserved Rab binding domain meric states of effectors, and detailed interactions with (RBD) at their C termini whose structure is unknown. Rabs are unique in all of these complexes. An emerging Here, we have determined the crystal structure of the theme in Rab recognition is the exploitation of noncon- RBD of FIP2 in complex with Rab11(GTP) by single served residues combined with structural diversity in wavelength anomalous diffraction methods. The over- conserved regions (switch 1, switch 2, interswitch) to all structure is a heterotetramer with dyad symmetry, achieve selective Rab binding by effectors (Pfeffer, arranged as a Rab11-(FIP2)2-Rab11 complex. FIP2 2005; Eathiraj et al., 2005; Merithew et al., 2001). forms a central a-helical coiled coil, with both helices In recent years, a novel set of effectors termed the contributing to the Rab11 binding patch on equivalent Rab11 family of interacting proteins (hereafter abbrevi- and opposite sides of the homodimer. Switch 1 of ated as FIPs) that contain a highly conserved C-terminal Rab11 is embedded between the two helices, while RBD has been identified (Prekeris et al., 2000, 2001; switch 2 remains flexible and is peripherally associ- Hales et al., 2001; Lindsay and McCaffrey, 2004b; Lind- ated with the effector. The complex reveals the struc- say et al., 2002). In contrast to their RBDs, FIPs are di- tural basis for Rab11 recognition by FIPs and suggests verse in sequence length and composition toward their the molecular mechanisms underlying endocytic recy- N termini, presumably a feature that underpins their spe- cling pathways. cific roles in Rab11-mediated vesicle trafficking. Rip11, FIP2, and RCP all contain C2 domains toward their N Introduction termini and are categorized as class I FIPs. They are pre- dominantly localized to the endocytic recycling com- The Rab family of small GTPases, which contains nearly partment (ERC), and their C2 domains have recently 70 proteins, constitutes the largest member of the Ras been observed to participate in this localization through superfamily (Bock et al., 2001; Pfeffer, 2005). Rabs are interactions with lipid bilayers enriched in anionic phos- anchored to lipid bilayers via C-terminal prenylation pholipids (Lindsay and McCaffrey, 2004a). The class II sites at cysteine residues, and they regulate various as- FIPs, FIP3 and FIP4, possess an ERM (ezrin-radixin- pects of membrane dynamics, including organelle struc- moesin) domain, EF hands, and a proline-rich region, ture, vesicle motility, docking, and fusion (Zerial and and they are found in the ERC, the trans-Golgi network, McBride, 2001). The Rab11 subfamily comprises three and centrosomes. Class II proteins interact with ADP ri- isoforms—Rab11a, Rab11b, and Rab25. Rab11a and bosylation factor (ARF) GTPases (Hickson et al., 2003), Rab11b are found in most tissue (Goldenring et al., allowing for potential crosstalk between the two signal- 1996; Lapierre et al., 2003), while Rab25 expression is ing pathways. Recent studies identified a role for FIP3 and FIP4 in endosomal trafficking to the cleavage furrow during cytokinesis via interactions with Rab11 and Arf6 *Correspondence: [email protected] (Horgan et al., 2004; Fielding et al., 2005). FIP1 lacks Structure 1274 both a C2 domain and EF hands, and it belongs to nei- Table 1. Data Collection and Refinement Statistics ther the class I nor the class II family (Wallace et al., 2002; Hales et al., 2001). Orthorhombic Trigonal Here, we have determined the structure of Rab11 with Space group P212121 P3121 the RBD of FIP2 in two different crystal forms. FIP2 is a Cell dimensions (A˚ ) 64.4, 91.1, 113.1 64.7, 64.7, 112.4 512 residue protein that contains a C2 domain at the N Wavelength (A˚ , Se peak) 0.97865 0.98175 ˚ terminus (residues 1–129), a myosin Vb binding region Resolution (A) 50–2.44 50–2.47 Completeness (%) 99.7 (98.5) 99.8 (100) (129–290), and an RBD at the C terminus (477–496), Rmerge (%) 10.2 (42.1) 6.7 (29.7) previously predicted to form an amphipathic a helix I/s(I) all data 8.8 16.3 (15.9) (Wallace et al., 2002; Lindsay and McCaffrey, 2004b; I/s(I) > 3 (% of data) 51.5 66.3 Junutula et al., 2004; Meyers and Prekeris, 2002). FIP2 Redundancy 13 (10) 16 (10) protein has been found to be essential for the recycling Refinement Statistics of vesicles bearing the chemokine receptor CXCR2 back Resolution (A˚ ) 50–2.44 50–2.47 to the plasma membrane (Fan et al., 2004). A ternary Number of reflections 25,444 10,206 complex of Rab11-FIP2-myosin Vb may provide the Models Rab11 Rab11 link between endosomes and the cytoskeleton to regu- (Glu7–Tyr173) (Asp6–Tyr173) late the delivery of vesicular cargo to the plasma mem- FIP2 FIP2 brane. This interaction would form the molecular basis (Arg468–Pro502) (Gly447–Ser503) for recruitment of leukocytes to the site of inflammation. FIP2 (Leu466–Pro502) The crystal structure of the Rab11-FIP2 complex reveals Rwork/Rfree (%) 22.6/27.9 19.6/25.3 that both a helices of the central helical dimer of FIP2 High-resolution shell (27.4/29.7) (22.2/33.0) contribute to the Rab11 binding patch, thus forming a Number of nonhydrogen 3,407 2,011 2-fold symmetric Rab11-(FIP2)2-Rab11 complex. Switch atoms 1 is embedded between the two a helices of FIP2, while Number of proteins 3,300 1827 switch 2 retains significant flexibility and reveals unprec- Number of GTP, ions 34 39 solute edented conformational changes from its unbound Number of waters 78 155 (GTP) conformation, as well as between the two crystal Average B factor (A˚ 2) forms in the Rab11-FIP2 complex. At the C-terminal Protein 39.2 47.6 half of the RBD, the a helix terminates and the polypep- Backbone 38.6 43.9 Side chain 40.2 47.1 tide adopts a 310 helix and a short b strand conformation that is perpendicular to the a helix and that packs against GTP 34.6 36.5 Mg2+ 29.3 36.3 b2 of Rab11. Finally, in a trigonal crystal form, the a-heli- Water 38.2 51.9 cal portion of the RBD is extended 20 residues further Rms deviations in the N-terminal direction relative to orthorhombic Bond lengths (A˚ ) 0.012 0.016 crystals. The conformational heterogeneity observed in Bond angles () 1.35 1.83 Rab11 and FIP2 likely reflects the dynamic nature of Coordinate error (ESU) ˚ ˚ Rab-effector association in cells, and it provides insight Based on Rfree 0.27 A 0.30 A into the molecular basis for endosomal trafficking Values in parentheses correspond to the statistics for the highest- pathways. resolution shell; orthorhombic = 2.53–2.44 A˚ , trigonal = 2.56–2.47 A˚ . Results and Discussion Rab11 and one FIP2 molecule. In the P212121 space group, the symmetry is broken and the helical axis be- Overview of Rab11-FIP2 Crystals comes a noncrystallographic dyad (180.0) that lies 4 Rab11a (1–173) and FIP2 (410–512) were coexpressed away from the crystallographic c axis. Thus, the asym- in E. coli and purified as a complex. Rab11 contained metric unit consists of two molecules each of Rab11 the Q70L substitution to favor the GTP form, and the and FIP2 in the orthorhombic space group. The amino subsequent structure revealed that endogenous GTP acid segments of Rab11 and FIP2 included in the refined had been incorporated during expression and purifica- models are indicated in Table 1.
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