Abstract
Small GTPases function as universal molecular switches due to the nucleotide dependent conformational changes of their switch regions that allow interacting proteins to discriminate between the active GTP-bound and the inactive GDP-bound states. Guanine nucleotide exchange factors (GEFs) recognize the inactive GDP-bound conformation whereas GTPase activating proteins (GAPs), and the GTPase effectors recognize the active GTP-bound state. Small GTPases are linked to each other through regulatory and effector proteins into functional networks that regulate intracellular membrane traffic through diverse mechanisms that include GEF and GAP cascades, GEF-effector interactions, common effectors and positive feedback loops linking interacting proteins. As more structural and functional information is becoming available, new types of interactions between regulatory proteins, and new mechanisms by which GTPases are networked to control membrane traffic are being revealed. This review will focus on the structure and function of the novel Rab11-FIP3-Rabin8 dual effector complex and its implications for the targeting of sensory receptors to primary cilia, dysfunction of which causes cilia defects underlying human diseases and disorders know as ciliopathies.
Keywords: Rab GTPases, GTPase effectors, Golgi, cilium, membrane trafficking
Abbreviations
- TGN
Trans-Golgi Network
Introduction
Small GTPases of the Ras, Rho, Rab and Arf families function as universal molecular switches that regulate effectively all cellular processes including signal transduction, cytoskeleton dynamics and membrane trafficking. Activity of Arf and Rab GTPases is tightly regulated by the guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and the GTPase effectors, which cooperate to regulate intracellular membrane traffic through diverse mechanisms that link interacting proteins into functional networks.1-3 Often, several of these regulatory properties are combined within large scaffold proteins, facilitating the ordered recruitment and activation of small GTPases during membrane trafficking.4 Coincidence detection and multiple interactions acting in concert regulate both the localization and the activity of Arf GTPases.5-7 Rab GTPases are specifically localized to different membrane domains where their activity alters the identity of transport membranes, thus connecting the different stages of specific transport pathways.8,9 To carry out their cellular functions, Arfs and Rabs interact with numerous and structurally diverse effector proteins through different but conserved binding modes.10 As more structural and functional information is becoming available, new types of interactions between regulatory proteins, and new mechanisms that link GTPases into regulatory circuits that control membrane traffic are being revealed.
Cilia Targeted Trafficking Complexes
Primary cilia are specialized organelles on the cell surface that have critical roles in sensing the extracellular environment and their dysfunction underlies critical disease pathways in human ciliopathies.11–14 The directional movement of sensory receptors to primary cilia is regulated by the sequential activation of Arf and Rab GTPases at multiple stages of trafficking.4 At least 3 macromolecular complexes regulated by small GTPases are involved in ciliary targeting: the IFT complex, the BBSome, and the ciliary targeting complex that participates in the trafficking of membrane proteins from the TGN to the cilium, which recognizes the conserved ciliary targeting signals of the light receptor rhodopsin and likely other ciliary sensory receptors.15–27 The latter complex serves as an effector of Arf4 and includes 3 other proteins25: i) the Arf GTPase activating protein (GAP) ASAP1,28–30 ii) the small GTPase Rab11a, and iii) the Rab11 and Arf effector FIP3.31,32 Rab11a activates Rab8 through the guanine nucleotide exchange factor (GEF) Rabin8,33 in a cascade of molecular interactions known as the Rab11-Rabin8-Rab8 ciliogenesis cascade.26,34–36 Rab8 is the ultimate Rab GTPase within this cascade and also regulates the final stages of polarized membrane traffic, carrier fusion and lumenogenesis.18,26,37–42 The Arf GAP ASAP1 functions as a GAP and an effector for Arf4, and serves as a platform upon which the ciliary targeting complex is assembled linking the early Arf4-dependent stages of ciliary targeting with the Rab11-Rabin8-Rab8 ciliogenesis cascade25,26 (Fig. 1A). FIP3 regulates ASAP1 interactions with the ciliary cargo, and stabilizes the transient ASAP1-Rab11-FIP3 complex to recruit the Rab8 GEF Rabin8.43 The evolutionary conserved Rab11-Rabin8-Rab8 ciliogenesis cascade parallels Ypt32p-Sec2p-Sec4p cascade in yeast budding.1 Thus, this ciliary targeting pathway combines an ancestral targeting module with the evolutionary more recent functions performed by Arf4, ASAP1, and the Arf and Rab11 effector FIP3, presumably to support the more complex cell organization.
The small GTPase Rab11 localizes to the trans-Golgi network (TGN) and endosomes, and functions in cytokinesis, membrane receptor recycling, cell polarity and ciliogenesis.4,44-48 The function of Rab11a is essential for the formation and integrity of vertebrate photoreceptors, where it directly interacts with the ciliary receptor rhodopsin, both in the GTP-bound and the GDP-bound state.25,26,43,49,50 The regulatory circuits that link Arf4 to Rab8 involve 2 Rab11a effectors: FIP3 and Rabin8. Rabin8 acts as a Rab11 effector and a scaffold for the Rab11a-Rab8 succession which is essential for ciliogenesis34–36 and fusion of transport carriers.26,37,38,43 During ciliogenesis, Rabin8 interacts directly, through its N-terminal domain, with the TRAPPC3, 9 and 10 subunits of the transport protein particle TRAPPII complex.34 The TRAPPC3, 9 and 10 subunits are homologs of yeast Bet3, Trs120 and Trs130, which are important for the GEF activity toward YPT1 (yeast homolog of Rab1) and YPT31/32 (yeast homolog of Rab11).51,52 Interestingly, the TRAPPII-binding N-terminal domain of Rabin8 is absent from Sec2 (yeast homolog of Rabin8). As TRAPPII mediates nucleotide exchange on the Ypt31 ortholog RabERAB11,53 it could also function as a GEF for vertebrate Rab11. TRAPPC10 has a longin domain (LD) that forms a platform for small GTPases in Rab GEFs,54 and a conserved, centrosome-targeting ASH domain.55 Thus, through its interaction with the TRAPPII complex, Rabin8 may also facilitate the selective activation of Rab11 in ciliogenesis.
The Rab11-FIP3-Rabin8 Dual Effector Complex
Whereas Rabin8 functions as a Rab11 effector at the final stages of ciliary trafficking, FIP3 interacts with Rab11a early in the ciliary pathway.25 FIP3 also functions as a Rab11 effector in cytokinesis56–59 and in the maintenance of the recycling compartment.60,61 The function of FIP3 as a Rab11 effector within the ciliary targeting complex was less clear until now. Given the known sequential interactions within the ciliary targeting complex, the model for its assembly suggested an initial recruitment of FIP3 that is subsequently replaced by Rabin8 to activate Rab8 and facilitate fusion of transport carriers with the plasma membrane.4,24 In this context, by serving as a Rab11 effector upstream of the conserved ciliogenesis cascade, FIP3 could provide a safety valve to block the premature assembly of the Rab11-Rabin8-Rab8 complex. However, recent structural and functional studies reveal that this is not the case because the 2 Rab11a effectors cooperate in carrying out Rab11a-related functions.43,62
The first surprise came from the study showing that FIP3 shapes the Rabin8 binding site within the ciliary targeting complex by significantly increasing Rabin8 interactions with both Rab11a and ASAP1.43 Furthermore, FIP3 and Rab11a bind Rabin8 separately, indicating that the 2 Rab11 effectors directly interact.43
In a concurrent study, the crystal structure of the Rab11-GMPPNP-FIP3-Rabin8 complex revealed simultaneous binding of FIP3 and Rabin8 effectors to activated Rab11.62 Direct interaction between Rabin8 and FIP3 effectors within the dual effector bound complex likely functions to stabilize the transient complexes and create a high avidity hub for cross talk of Arf and Rab GTPases in ciliary trafficking (Fig. 1).
Simultaneous Binding of FIP3 and Rabin8 Effectors to Active Rab11
A hallmark of small GTPases is the nucleotide dependent conformational change of the switch regions that allows effectors to discriminate between the active GTP-bound and the inactive GDP-bound states.63 Small GTPases often have multiple effectors, but because of the limited accessible surface area shaped by the switch regions at the G-site, the binding of different effectors is thought to be sequential and mutually exclusive. Numerous effectors have been described for Rab11 including FIPs, Rabin8, Sec15 and Rab11BP/WDR44.32,35,64–66 Two of these effectors, FIP3 and Rabin8, have been implicated in ciliogenesis and in the trafficking of membrane proteins from the TGN to the cilium.26,35,43 However, recent new data demonstrate that FIP3 and Rabin8 can associate with Rab11 at the same time.43,62 Pull-down experiments, size exclusion chromatography (SEC) and isothermal titration calorimetry (ITC) experiments revealed that the C-terminal Rab11-effector domain of Rabin8 (Rabin8C) binds a preformed Rab11-FIP3 complex to form a ternary Rab11*-GMPPNP-FIP3-Rabin8C complex.43,62 Interestingly, Rabin8C has ∼4-fold higher affinity for Rab11-FIP3 than for Rab11 alone, suggesting that FIP3 and Rabin8 either interact directly, or that the binding of FIP3 to Rab11 induces a conformational change in Rab11 that strengthens the Rabin8 association. Pull-down experiments suggested that the former possibility is most likely correct, as a direct interaction between FIP3 and Rabin8 was observed.43,62 Moreover, the regions of Rab11 that interact with Rabin8 do not undergo conformational changes upon FIP3 effector binding.59,67,68 These results are in agreement with a model where FIP3 and Rabin8 effectors simultaneously associate with Rab11 (Fig. 1).
Rabin8 C-terminal Domain is a Novel Low-Affinity Rab-effector
The fact that FIP3 and Rabin8 are able to bind Rab11 at the same time raises the question of how this is achieved structurally. Previously published crystal structures of Rab11 bound to FIP2 or FIP3 revealed a canonical effector-binding site with extensive contacts with switch I and II regions, which leave little space for simultaneous Rabin8 binding at the G-site.59,68,69 However, although Rabin8 as an effector does have a preference for GTP- vs. GDP-bound Rab11, the Kd of 40μM demonstrates weak affinity that could be the result of a relatively small Rabin8-binding-surface on Rab11*GTP.62 Indeed, the crystal structure of the Rab11-Rabin8 complex revealed a relatively small (∼600Å2) binding interface utilizing mostly non-switch region residues (Fig. 2). The C-terminal domain of Rabin8 adopts a novel fold that interacts with Rab11 via a non-canonical effector-binding site through contacts with 2 residues of switch I (L38 and E39), 4 residues of a non-switch-region loop connecting β5 and α4 of Rab11 (L128, R129, H130 and L131), and no contacts with switch II. Additionally, several main-chain hydrogen bonds are facilitated by β strand β2 of Rabin8 and residues 129–134 of Rab11 (Fig. 2). The Rabin8 binding-site on Rab11 is thus neighboring the canonical effector-binding site suggesting how dual effector binding to Rab11 may be achieved. The Rab11*GMPPNP-FIP3-Rabin8 crystal structure revealed how the 2 FIP3/Rabin8 effectors bind Rab11 at neighboring sites closely approaching and interacting with each other (Fig. 1B).62 FIP3 binds GTP-bound Rab11 with a Kd of ∼0.3μM,59 which is 2 orders of magnitude higher than the affinity of Rabin8 for Rab11.62 It is thus conceivable that Rab11 first binds FIP3 to form a Rab11-FIP3 complex that subsequently recruits Rabin8 to form the Rab11-FIP3-Rabin8 complex. This notion is supported by the fact that Rab11-FIP3 complex has 4-5 fold higher affinity for Rabin8 than Rab11 alone.43,62 In this respect, part of the preference of Rabin8 for GTP-bound Rab11 is indirectly assured via binding of the canonical FIP3 effector. The Rabin8 C-terminal domain thus represents an unusual Rab11 effector that binds at an unconventional effector-binding site with low affinity.
Rabin8C and PI4KIII Utilize the same Binding Surface on Rab11
Comparison of the Rab11*-*GMPPNP-Rabin8 structure to previously determined structure of Rab11 complexes revealed that Rabin8 binds Rab11 at a similar site to that of the phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ)62,70 (Fig 3). PI4KIIIβ catalyzes the phosphorylation of phosphatidylinositol to generate phosphatidylinositol4-phosphate (PI4P), a reaction important for the formation and function of the Golgi where PI4KIIIβ is localized and where it interacts with Rab11.71 Despite different folds of PI4KIIIβ and Rabin8, both proteins contact a similar set of Rab11 residues including L38, E39, L128, H130 and L131 (Fig. 3). Interestingly, PI4KIIIβ was reported not to be an effector for Rab11 as the binding affinity for Rab11*GTP was only 3-4 fold higher than for Rab11*GDP in agreement with the fact that most contacts are with non-switch-region residues.70 This relatively small but significant preference of PI4KIIIβ for GTP- vs. GDP-bound forms of Rab11 is likely a result of contacts with L38 and E39 of switch I. Given the fact that Rabin8 and PI4KIIIβ bind to similar sites on Rab11 with contacts to L38 and E39 of switch 1 an interesting question is to which degree Rabin8 prefers GTP- vs. GDP-bound Rab11.
Specificity of Rabin8 for GTP-bound vs. GDP-bound Rab11
Rabin8 was reported to be an effector of Rab11 as it recognizes the GTP-bound and not the GDP-bound state of the small GTPase in pull-down experiments.35,62 A Kd value for the Rab11*GDP-Rabin8 complex has not been published but is, based on pull-down experiments, clearly much higher than the Kd of 40μM measured for the Rab11*GMPNP-Rabin8 complex.62 Although it is hard to measure the low affinity of Rabin8 for Rab11*GDP accurately, ITC experiments suggest a Kd for the Rab11*GDP-Rabin8 complex in the 200-400μM range (M. Vetter and E. Lorentzen, unpublished data). This indicates that the affinity of Rabin8 for Rab11*GTP is 5-10 fold higher than for Rab11*GDP. The specificity of effectors for the GTP-bound state of small GTPases arises from the unique conformation adopted by the switch regions when bound to GTP, which shape the binding surface to engage different effectors in a specific manner. Although the GDP-bound state often results in disordered switch regions,72 some small GTPases adopt well-ordered but different conformations of the switch regions depending on nucleotide state. One such case is Arl6 where only the GTP-bound conformation can recruit the BBSome to membranes via the BBS1 effector protein because the GDP-bound conformation prevents BBS1-binding due to molecular clashes.19,22 Importantly, the switch regions are also ordered in crystal structures of both GDP- and GTP-bound Rab11.67,73 The conformational differences in switch regions between different nucleotide states of Rab11 are relatively modest with a root-mean-square-deviation (rmsd) between cα-atoms of maximum 5Å (Fig 2). Given the fact that Rabin8 does not contact switch 2 of Rab11, the preference for GTP-bound Rab11 is likely attributed to the contacts with L38/E39 of switch 1 (Fig. 2). By comparing the confirmation of L38/E39 between GDP- and GTP-bound Rab11, it is striking that only the side-chain of E39 but not the side-chain of L38 displays a nucleotide dependent conformational change (Fig 2). In the GTP-bound form of Rab11, the side-chain of E39 points toward residues 430–431 of Rabin8 and makes 2 hydrogen bonds of 3Å in length with backbone NH groups. In the GDP-bound form of Rab11, E39 adopts a different rotameric conformation that points away from Rabin8 and would increase the hydrogen bonding distances to 5–6Å (Fig 2). Notably, the Rabin8-binding competent conformation of E39 is not induced by Rabin8-binding as it adopts the same rotamer in Rab11*GTP not bound to any effectors.67 It appears likely that E39 of Rab11 is important for the nucleotide dependent association with Rabin8.
Rabin8 Effector Binding is Specific for Rab11
Yeast-2-hybrid analysis of Rabin8 binding to a host of different Rab proteins revealed a strong specificity for Rab11.34 To address the molecular basis of this specificity we superimposed the structure of Rab11-Rabin8 with known structures of different Rab family members in the GTP-bound state (Fig 4A). The result reveals that there are no major clashes between Rabin8 and other members of the Rab superfamily such as Rab4, Rab6, Rab8, Rab14 or Rab25 suggesting that complex formation with Rabin8 is in principle possible (Fig 4A). However, the residues utilized by Rab11 to bind Rabin8 are not well conserved in other Rab families (Fig 4B). In particular the Rabin8-interacting switch 1 residues of Rab11 (L398 and E39) are poorly conserved (Fig 4B). E39 is often replaced by an aspartic acid that is not well positioned to make tight hydrogen bonds with residues 430–431 of Rabin8. L38 of Rab11 engages in hydrophobic contacts with residues from Rabin8 but is replaced by a hydrophilic residue in most other Rabs. Additionally, sequence alignment of different Rabs demonstrates that the Rabin8/PI4KIIIβ binding residues are only conserved in Rab11 orthologues and not in Rabs from different families, which suggests that the Rabin8/PI4KIIIβ binding site is unique to Rab11. Interestingly, the Rabin8-binding residues of Rab11 are well conserved in Ypt32, which is the yeast homolog of Rab11 (Fig 4C). This indicates that the molecular mechanism of Sec2 (yeast homolog of Rabin8)-recruitment by Ypt32 to activate Sec4 (yeast homolog of Rab8) is evolutionarily conserved. Surprisingly, the Rabin8 binding residues of Rab11 are also conserved in organisms like Chlamydomonas reinhardtii and Arabidopsis thaliana that do not appear to have a Rabin8 homolog. The genomes of Chlamydomonas reinhardtii and Arabidopsis thaliana do however encode putative PI4KIIIβ homologs with the Rab11-binding helical domain conserved. Given that Rab11 utilized the same residues for Rabin8 and PI4KIIIβ binding it appears likely that the binding site in Chlamydomonas reinhardtii and Arabidopsis thaliana Rab11 is conserved to bind PI4KIIIβ. Collectively, Y2H and bioinformatics analyses suggest that Rabin8 binding is specific to Rab11 and that the recruitment of Rabin8 by Rab11 to activate Rab8 is an evolutionarily ancient pathway in exocytosis.
Regulation of Rabin8
Rabin8 is recruited to the membrane by Rab11a and interacts with specific phospholipids such as phosphatidylserine (PS, strong interaction) and phosphatidic acid (PA, weak interaction).74 The amino acids 251–460 were suggested to encompass a minimum PS-binding domain of Rabin8 based on binding experiments with truncated protein constructs.74 PS recognition is typically mediated by Ca2+-dependent C2 domains or by basic stretches of residues.75 Given that the structure of the C-terminal Rabin8 domain (residues 290–460) does not display a PS-binding domain, residues 250–290 likely encompass the PS-binding region. Rabin8250-290 is a part of the linker region (predicted to be disordered) that connects the central GEF domain to the C-terminal Rab11-effector domain (Fig. 5). The flexible nature of Rabin8250-290 probably allows this region to approach the membrane to recognize PS. Examination of the Rabin8250-290 sequence reveals a basic stretch of residues rich in lysines (260-KTPFKKGHTRNKS-272, human Rabin8 numbering) that could serve as the PS-recognition motif (Fig. 5).
Remarkably, NDR2-mediated phosphorylation of Rabin8 regulates the switch in binding specificity of Rabin8 from PS to the Sec15 component of the exocyst complex that mediates carrier tethering at the periciliary plasma membrane.36,74,76 NDR2 (also known as STK38L) was identified as a canine retinal degeneration gene corresponding to human ciliopathy Leber congenital amaurosis (LCA) characterized by early-onset blindness,77,78 indicating that the switch in binding partners of Rabin8 has a crucial role in ciliary membrane trafficking. The site of NDR2 phosphorylation, S272, lies close to the polybasic stretch of residues within the structurally disordered region of Rabin8 (Fig. 5), suggesting that NDR2 phosphorylation directly regulates PS-binding through the introduction of negative charges. Both S272 and the polybasic residues are well conserved in Rabin8 proteins from different organisms (but not in the Sec2 yeast homolog that instead of PS binds PI4P via its C-terminal residues 258–45079) suggesting an evolutionary conserved mechanism of regulation in higher eukaryotes (Fig. 5). Ypt32 and Sec15 compete for binding to Sec2 and phosphorylation of Sec2 within the linker region directs a switch in binding from Ypt32 to Sec15.79,80 This mode of action is not conserved, as Sec15 is a common effector for Rab11 and Rab8,64,65 which differs from Ypt32 that does not associate with the exocyst complex. Interestingly, phosphorylation of both Rabin8 and Sec2 acts as a switch in binding to Sec15, but, unlike in yeast, in higher eukaryotes Sec15, Rab11a and Rabin8 diversify to cooperate in ciliary membrane trafficking.
Concluding Remarks
Interaction networks of small GTPases are organized by regulatory proteins and effectors that form signaling junctions for communication between Arf and Rab GTPases. Comprehensive structural and functional data explain at the molecular level how regulatory circuits that function in ciliary targeting converge to form a signaling junction through the Rab11a-FIP3-Rabin8 dual effector complex. The signaling output of Rab11a through the Rabin8-FIP3 complex may control ciliary targeting by selectively allowing the cargo presented in the context of Arf4 and its effector FIP3 to engage Rabin8 and activate Rab8, ultimately facilitating fusion of transport carriers with the periciliary plasma membrane. Future research will reveal the level of conservation of dual effector complexes in linking interacting proteins to control the activity and output of Rab GTPases.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Funding
Supported by the NIH grant EY-12421 to DD, and by the European Research Council (ERC grant 310343) and by the EMBO Young Investigator program grant to EL.
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