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Structural and Functional Analyses of the N-Terminal Domain of the a Subunit of a Bacillus Megaterium Spore Germinant Receptor

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Structural and Functional Analyses of the N-Terminal Domain of the a Subunit of a Bacillus Megaterium Spore Germinant Receptor Structural and functional analyses of the N-terminal domain of the A subunit of a Bacillus megaterium spore germinant receptor Yunfeng Lia, Kai Jina, Abigail Perez-Valdespinoa,1, Kyle Federkiewicza, Andrew Davisa, Mark W. Maciejewskia, Peter Setlowa, and Bing Haoa,2 aDepartment of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT 06030 Edited by Richard Losick, Harvard University, Cambridge, MA, and approved April 30, 2019 (received for review March 1, 2019) Germination of Bacillus spores is induced by the interaction of functional GRs, GerA, GerB, and GerK, have been extensively specific nutrient molecules with germinant receptors (GRs) local- studied. The GerA GR triggers spore germination in response to ized in the spore’s inner membrane. GRs typically consist of three L-alanine or L-valine, while the GerB and GerK GRs act cooperatively subunits referred to as A, B, and C, although functions of individ- to trigger germination with a cogerminant mixture of L-asparagine, + ual subunits are not known. Here we present the crystal structure D-glucose, D-fructose, and K ions (AGFK). Interestingly, all three of the N-terminal domain (NTD) of the A subunit of the Bacillus B. subtilis GRs are colocalized primarily in a single cluster termed a megaterium GerK3 GR, revealing two distinct globular subdomains “germinosome” in the inner membrane (IM) of spores along with bisected by a cleft, a fold with strong homology to substrate- the auxiliary germination protein GerD (10). Loss of any subunit of binding proteins in bacterial ABC transporters. Molecular docking, a particular GR generally destabilizes the other two subunits and chemical shift perturbation measurement, and mutagenesis cou- abolishes the activity of the entire GR but has minimal effects on the pled with spore germination analyses support a proposed model function of other GRs (11, 12). Despite a clear understanding of that the interface between the two subdomains in the NTD of GR their roles in spore germination, the mechanism whereby GRs A subunits serves as the germinant binding site and plays a critical recognize specific germinants and initiate the germination cascade role in spore germination. Our findings provide a conceptual remains largely unknown. MICROBIOLOGY framework for understanding the germinant recruitment mecha- The A, B, and C subunits of GRs exhibit minimal sequence nism by which GRs trigger spore germination. homology with proteins of known function, although both within and across species individual GR subunits exhibit significant Bacillus | spores | spore germination | spore germinant receptor sequence and predicted topology homologies with the corre- sponding subunits of other GRs (9) (current study). Bio- ormation of metabolically dormant endospores is common to informatic and membrane topological analyses show that the A Fmany species in the Firmicutes phylum, in particular Bacil- and B subunits of the GRs are integral membrane proteins, lales and Clostridiales (1). These spores can survive prolonged nutrient starvation and are resistant to a variety of antimicrobial Significance treatments due to their special outer layers and unique features of the spore core. However, spores are capable of monitoring the Bacterial endospores are found as normal inhabitants nutritional state of their surroundings and returning to a meta- throughout the environment, and some are vectors leading to bolically active state through a series of events termed germi- food spoilage, food poisoning, and infectious diseases. Pro- nation, when environmental conditions once again favor moting efficient germination of spores could sensitize spores vegetative growth (2, 3). Notably, spores lose many of their re- for practical inactivating measures. Specific nutrient germi- sistance properties during germination and can then be easily nants that trigger spore germination are recognized by cog- eliminated by routine decontamination methods. Many members nate germinant receptors (GRs). In this work, we report a of Bacillales and Clostridiales genera are found in the environ- structure-based mechanism for GR-mediated germinant bind- ment and some can be human commensals; importantly, spores ing and recruitment. Crystal structure, molecular docking, and of some of these species can be crucial in causing food spoilage biophysical and genetic analyses indicate that the N-terminal as well as some infectious diseases and intoxications of public domain of GR A proteins likely possesses a binding pocket that health concern (1). Discovery and development of novel agents accommodates specific germinant molecules at the interface that promote highly efficient germination of spores in pop- between its two subdomains. These results can be explored for ulations could facilitate efforts to render spores more susceptible the development of germinant analogues as either potentia- to benign disinfection measures, and thus reduce transmission of tors or inhibitors of spore germination. spores that can cause some serious human diseases (4, 5). Author contributions: Y.L., P.S., and B.H. designed research; Y.L., A.P.-V., K.F., A.D., In nature, Bacillus spore germination is irreversibly triggered M.W.M., and B.H. performed research; Y.L., K.J., A.P.-V., M.W.M., and B.H. analyzed data; when specific small-molecule nutrients called germinants are and P.S. and B.H. wrote the paper. recognized by germinant receptors (GRs) located in the inner spore The authors declare no conflict of interest. membrane, resulting in the release of dipicolinic acid (DPA) from the This article is a PNAS Direct Submission. endospore core and degradation of the peptidoglycan cortex (3, 6, 7). Published under the PNAS license. All known spores of Bacillales and most Clostridiales species have Data deposition: The atomic coordinates and structure factors have been deposited in the GerA-type GRs whose coding genes are typically arranged in tricis- Protein Data Bank, http://www.wwpdb.org/ (PDB ID code 6O59). tronic operons that encode three protein components termed A, B, 1Present address: Department of Biochemistry, Escuela Nacional de Ciencas Biológicas del and C, and in some cases perhaps a D subunit (7, 8). Multiple GR Instituto Politécnico Nacional, 11340 Mexico City, Mexico. isoforms with distinct or partially overlapping germinant specificities 2To whom correspondence may be addressed. Email: [email protected]. have been described (2, 9); SI Appendix,TableS1lists the number of This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. the A subunits of GRs identified in Bacillales and Clostridiales species. 1073/pnas.1903675116/-/DCSupplemental. In Bacillus subtilis, the model organism for spore research, three www.pnas.org/cgi/doi/10.1073/pnas.1903675116 PNAS Latest Articles | 1of10 Downloaded by guest on September 25, 2021 whereas the C proteins are peripheral membrane proteins with was refined to an R factor of 20.5% and a free R value of 22.7% an N-terminal diacylglycerol anchor (13, 14). While the B subunits (SI Appendix, Table S2). NTD are predicted to have transmembrane (TM) helices throughout GerK3A forms a butterfly-shaped architecture consisting the entire protein, the A subunits consist of a core TM domain of two distinct globular subdomains (N1 and N2) connected by a flanked by a large hydrophilic N-terminal domain (NTD) and a flexible linker (Fig. 1B). Each of these two subdomains contains short C-terminal tail. The crystal structure of the C subunit of the a central five-stranded antiparallel β-sheet flanked by α-helices B. subtilis GerB GR (GerBC) revealed a previously uncharac- on each side (Fig. 1C). The N1 domain (residues 26–152) is terized type of protein fold consisting of three distinct α/β mixed formed by the central β-sheet arranged with a topology of domains (15). A number of site-directed mutagenesis studies of A S1S2S4S5S3, with helices H1 and H5 flanking on one side and H2, and B subunits of GRs (11, 12, 16, 17), aided by the limited se- H3, and H4 on the other side. In the N2 domain (residues 170– quence homology between the B subunits of GRs with the su- 296), the central β-sheet has the same topology (S6S7S9S10S8) perfamily of single-component amino acid transporters (18), have surrounded by helices H6 and H10 as well as H7, H8, and H9. led to the speculation that GRs may possess a transporter-related The 16-residue linker region (residues 153–169) between the function. However, the precise function of each GR subunit and N1 and N2 domains is not visible in the electron density map and how they interact with germinants have remained elusive. therefore must be disordered. To further probe the role of the individual GR subunits in Despite their low sequence identity (19.2%), the N1 and spore germination, we have now determined the crystal structure N2 domains share essentially identical secondary-structure to- of the conserved N-terminal soluble domain of the A subunit of pology and connectivity and superimpose very well with an rmsd NTD the Bacillus megaterium GerK3 GR (GerK3A ; lacking the of ∼1.89 Å over 96 aligned Ca positions (Fig. 2A and SI Ap- extreme N-terminal 25 residues), the first structure of any GR A pendix, Fig. S2). The 24 invariant residues shared between the NTD subunit. GerK3A consists of two distinct three-layer αβα N1 and N2 domains are located throughout the entire sub- sandwich subdomains separated by a deep cleft. Interestingly, domains (SI Appendix, Fig. S2). The most notable structural this protein shares significant structural similarity to substrate- difference in two subdomains is in the two outer helices (H3 and binding proteins that serve as receptors for membrane-associated H4 in the N1 domain vs. H8 and H9 in the N2 domain) in which small-molecule transporters and signal transducers (19–21). Our H8 and H9 exhibit a more relaxed conformation (Fig. 1B). biochemical and biophysical data strongly suggest that amino acid residues lining the cleft between the two subdomains of the NTDs of the A subunits are involved directly in the recognition and binding of germinants.
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