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Structural Basis for the Alternating Access Mechanism of the Cation Diffusion Facilitator Yiip

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Structural Basis for the Alternating Access Mechanism of the Cation Diffusion Facilitator Yiip Structural basis for the alternating access mechanism of the cation diffusion facilitator YiiP Maria Luisa Lopez-Redondoa,1, Nicolas Coudraya,1, Zhening Zhanga,2, John Alexopoulosa, and David L. Stokesa,3 aSkirball Institute, Department of Cell Biology, New York University School of Medicine, New York, NY 10016 Edited by Robert M. Stroud, University of California, San Francisco, CA, and approved January 31, 2018 (received for review August 24, 2017) YiiP is a dimeric antiporter from the cation diffusion facilitator representatives. Both superfamilies are characterized by internal family that uses the proton motive force to transport Zn2+ across sequence repeats which fold into two distinct domains. The con- bacterial membranes. Previous work defined the atomic structure of formational changes from IF to OF states are described as either + an outward-facing conformation, the location of several Zn2 bind- rocking-bundle or elevator-like movements of one domain relative ing sites, and hydrophobic residues that appear to control access to to the other, and these movements typically involve coordinated, the transport sites from the cytoplasm. A low-resolution cryo-EM symmetric structural changes in the respective repeats (15–17). structure revealed changes within the membrane domain that were CDF transporters, however, do not have an obvious sequence associated with the alternating access mechanism for transport. In repeat, and although many are reported to form homodimers, an the current work, the resolution of this cryo-EM structure has been X-ray structure of YiiP shows that independent transport sites are extended to 4.1 Å. Comparison with the X-ray structure defines the present within each monomer (18, 19). differences between inward-facing and outward-facing conforma- More specifically, the X-ray structure of E. coli YiiP showed a tions at an atomic level. These differences include rocking and twist- dimer that is stabilized by a conserved salt bridge at the cyto- + ing of a four-helix bundle that harbors the Zn2 transport site and plasmic membrane surface and interactions between C-terminal, controls its accessibility within each monomer. As previously noted, cytoplasmic domains (CTDs). The transmembrane (TM) do- membrane domains are closely associated in the dimeric structure mains were splayed apart with no intermolecular interactions. + from cryo-EM but dramatically splayed apart in the X-ray structure. Zn2 ions were bound at the transport sites within each TM Cysteine crosslinking was used to constrain these membrane do- domain, and their accessibility suggested that this structure rep- mains and to show that this large-scale splaying was not necessary resented an OF conformation. A subsequent structure of a closely for transport activity. Furthermore, dimer stability was not compro- related YiiP from Shewanella oneidensis (45% identity) was pro- mised by mutagenesis of elements in the cytoplasmic domain, sug- duced by our laboratory using cryo-EM images of tubular, 2D gesting that the extensive interface between membrane domains is crystals in a lipid environment (20). Although this cryo-EM a strong determinant of dimerization. As with other secondary structure was at low resolution (13 Å), it was clear that the TM transporters, this interface could provide a stable scaffold for move- domains adopted a closely apposed conformation, whereas the ments of the four-helix bundle that confers alternating access of cytoplasmic domain and its dimer interface were very similar to these ions to opposite sides of the membrane. the X-ray structure. Constrained fitting of the X-ray structure to the cryo-EM map suggested that it represented an IF conforma- zinc homeostasis | membrane transport | alternating access mechanism | tion, brought about by rocking movements of a four-helix bundle cysteine crosslinking | cryo-EM in the TM domain of each monomer. Thus, comparison of the two structures led to a transport model that involved large-scale scis- he cation diffusion facilitator (CDF) family comprises sec- soring of the TM domains accompanied by smaller-scale rocking Tondary transporters that maintain homeostasis for transition metal ions. The family was initially identified from operons as- Significance sociated with the czc metal resistance determinant (1) and later characterized by a phylogenetic analysis that highlighted diversity + Zn2 is a micronutrient that plays important roles throughout in ion selectivity and cell localization (2). The CDF family is now the body. We are interested in molecular mechanisms by which recognized to comprise three broad groups (3): Group 1 contains 2+ + appropriate levels of Zn are maintained in cells. We have Zn2 transporters from humans [Znt1-10 (4)], fungi [Zhf, Zrc1, combined structural and functional studies to deduce the phys- and Cot1 (5)], plants [metal transport proteins (MTPs) (6)], and 2+ ical changes that a bacterial transporter uses to carry Zn across bacteria [e.g., ZitB (7)]. Group 2 includes the well-characterized Escherichia coli – cell membranes. We have identified parts of the molecule that YiiP (FieF) from (8 10) as well as transporters remain static and characterized the movements of other parts that have been reported to transport or mediate tolerance to a 2+ + + + + + that bind Zn ions and allow them to cross the membrane. wide range of ions, including Zn2 ,Cd2 ,Fe2 ,Co2 ,andNi2 . Group 3 is dominated by plant and fungal transporters that pro- Author contributions: M.L.L.-R., N.C., and D.L.S. designed research; M.L.L.-R., N.C., Z.Z., 2+ vide tolerance to Mn (11). All CDF transporters are thought to J.A., and D.L.S. performed research; M.L.L.-R., N.C., Z.Z., J.A., and D.L.S. analyzed data; and be antiporters that use the proton motive force to export their M.L.L.-R., N.C., and D.L.S. wrote the paper. respective transition metal ions from the cytoplasm (12, 13). The authors declare no conflict of interest. The alternating access mechanism represents a paradigm for This article is a PNAS Direct Submission. secondary transporters, in which substrates are carried across the Published under the PNAS license. membrane as the protein cycles between inward-facing (IF) and Data deposition: Crystallography, atomic coordinates, and structure factors have been outward-facing (OF) conformations (14). Definition of these deposited in the Protein Data Bank, www.wwpdb.org (PDB ID code 5VRF), and in the conformations is a first step toward characterizing the transport EM Data Bank (EMDB code EMD-8728). mechanism, which ultimately also requires understanding of stable 1M.L.L.-R. and N.C. contributed equally to this work. intermediate states as well as the energy landscape that governs 2Present address: New York Structural Biology Center, New York, NY 10027. transitions between these states. In the case of the major facili- 3To whom correspondence should be addressed. Email: [email protected]. tator superfamily (MFS) and amino acid-polyamine-organocation This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. (APC) superfamily, structural studies have gone a long way to- 1073/pnas.1715051115/-/DCSupplemental. ward providing the relevant structural information for individual Published online March 5, 2018. 3042–3047 | PNAS | March 20, 2018 | vol. 115 | no. 12 www.pnas.org/cgi/doi/10.1073/pnas.1715051115 Downloaded by guest on September 26, 2021 + of this four-helix bundle to achieve alternating access of the Zn2 Type 2 transport sites. A more recent study of hydroxyl radical footprinting A identified specific residues along the M5 helix; differing reactivities + in the presence and absence of Zn2 suggested that rigid-body movements of M5 restricted access to the transport sites in the OF state (21). For this report, we sought to further characterize conforma- + tional changes underlying alternating access and Zn2 transport by YiiP. To start, we obtained a high-resolution structure of the IF state using cryo-EM images of the membrane-bound, helical crystals. This structure allowed us to build an atomic model and to evaluate detailed structural differences relative to the OF state from X-ray crystallography. This comparison indicates Type 1 nonrigid-body movements among the four-helix bundle that + surrounds the Zn2 transport site. To assess the functional im- plications of the apparent scissoring motion of the TM domain, we generated cysteine substitutions and made intermolecular B C 2,2; 0 crosslinks in conjunction with in vitro analysis of transport ac- 1,2; 5 tivity. Finally, we made mutations to elements that appear to 1,1; -3 1,1; 0 stabilize the homodimer, to elucidate the structural basis for this 0,1; 3 0,1; 5 -1,1; 9 2,0;-10 -1,1;10 conserved feature of the CDF superfamily. Our results indicate 2,0;-12 that scissoring of TM domains is not essential for transport. We 1,0; -5 1,0; -6 have developed a hybrid model for the OF state that illustrates conformational changes that we believe underlie the alternating access mechanism of YiiP. Results Type 1 Type 2 Cryo-EM Structure of YiiP. YiiP from S. oneidensis was expressed in E. coli, and after purification, detergent-solubilized preparations were reconstituted into bilayers of dioleoylphosphatidyl glycerol DE (DOPG) at a lipid-to-protein ratio of 0.5 (wt/wt) by dialysis. As 1.0 3.75Å 3.5 Å 4.0 Å 4.25Å detergent was removed, YiiP assembled into extended 2D arrays 3.25Å within the lipid bilayer. These bilayers adopted a tubular mor- phology, thus twisting the 2D arrays of YiiP into a helical ar- rangement. Cryo-EM imaging revealed two distinct helical symmetries, denoted types 1 and 2 (Fig. 1). For 3D reconstruction, 0.5 FSC overlapping masks were applied to images of individual tubes to produce a set of single particles for use with iterative real-space ZnB reconstruction algorithms (22). These single particles were sub- jected to 2D classification, which revealed the presence of sub- 0.0 20 7.6 4.7 3.4 types for both type 1 and type 2 (denoted types 1a, 1b, 1c, 2a, and 2.7 2.2 ZnC 2b; Fig.
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