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Correlated Protein Conformational States and Membrane Dynamics Correlated protein conformational states and membrane dynamics during attack by pore-forming toxins Ilanila I. Ponmalara, Ramesh Cheerlab, K. Ganapathy Ayappaa,b,1, and Jaydeep K. Basuc,1 aCenter for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India; bDepartment of Chemical Engineering, Indian Institute of Science, Bangalore 560012, India; and cDepartment of Physics, Indian Institute of Science, Bangalore 560012, India Edited by Alan R. Fersht, University of Cambridge, Cambridge, United Kingdom, and approved May 21, 2019 (received for review December 22, 2018) Pore-forming toxins (PFTs) are a class of proteins implicated in a model lipid membranes have been used to ascertain the presence wide range of virulent bacterial infections and diseases. These of prepore and pore structures with atomic force microscopy toxins bind to target membranes and subsequently oligomerize (AFM) (7–10). The LLO pore states can exist either as par- to form functional pores that eventually lead to cell lysis. While tially oligomerized arcs or complete pores, with sizes ranging the protein undergoes large conformational changes on the from 40 to 80 nm (9) and selective influx of dyes into giant bilayer, the connection between intermediate oligomeric states unilamellar vesicles (GUVs) exposed to LLO confirm the pres- and lipid reorganization during pore formation is largely unex- ence of functional oligomeric intermediates (10). A widely used plored. Cholesterol-dependent cytolysins (CDCs) are a subclass method to probe protein-conformational states and their tran- of PFTs widely implicated in food poisoning and other related sitions is Forster¨ resonance energy transfer (FRET) (11–14). infections. Using a prototypical CDC, listeriolysin O (LLO), we Although FRET has been extensively used to study bulk proteins, provide a microscopic connection between pore formation, lipid fewer reports are available on intermolecular FRET between dynamics, and leakage kinetics by using a combination of Forster¨ lipids and proteins (15, 16). Recently, FRET has been used resonance energy transfer (FRET) and fluorescence correlation to study oligomeric intermediates of cytolysin A, an α-PFT in spectroscopy (FCS) measurements on single giant unilamellar vesi- detergent (17). BIOPHYSICS AND cles (GUVs). Upon exposure to LLO, two distinct populations of To determine the process of cell lysis induced by LLO pore GUVs with widely different leakage kinetics emerge. We attribute formation, one needs to decipher the lipid-mediated membrane COMPUTATIONAL BIOLOGY these differences to the existence of oligomeric intermediates, response. Vesicle-leakage experiments can probe the kinetics sampling various membrane-bound conformational states of the of pore formation and cellular lysis without revealing direct protein, and their intimate coupling to lipid rearrangement and information about oligomeric intermediates or lipid response dynamics. Molecular dynamics simulations capture the influence (18–22). Recent superresolution-stimulated emission depletion– of various membrane-bound conformational states on the lipid fluorescence correlation spectroscopy (FCS) experiments (7, and cholesterol dynamics, providing molecular interpretations to 23–25) on supported lipid bilayers (SLBs) have revealed the the FRET and FCS experiments. Our study establishes a micro- extent of induced dynamic heterogeneity and protein-mediated scopic connection between membrane binding and conforma- lipid reorganization due to pore formation. Deviations from tional changes and their influence on lipid reorganization during Brownian diffusion are observed at length scales between 100 PFT-mediated cell lysis. Additionally, our study provides insights and 200 nm. Molecular dynamics (MD) simulations, sampling into membrane-mediated protein interactions widely impli- cated in cell signaling, fusion, folding, and other biomolecular Significance processes. Listeriolysin O (LLO), a pore-forming toxin expressed by pore-forming toxin j giant unilamellar vesicle j Forster¨ resonance energy Listeria monocytogenes, plays a critical role in assisting bac- transfer j fluorescence correlation spectroscopy teria escape the phagocytic vacuole. To evolve a suitable defense mechanism against LLO-mediated infections, a micro- ore-forming toxins (PFTs) are perhaps the earliest known scopic understanding of the process of vacuole disruption Pproteins implicated in bacterial pathogenesis and defense and consequent immune evasion is needed. Using a combina- against the host immune system (1). They are cytolytic in nature, tion of imaging and dye-leakage kinetics on giant unilamellar with their primary virulence manifesting through unregulated vesicles along with atomistic simulations, we illustrate the pore formation and cell lysis (2). PFTs are classified as either α- intimate coupling between membrane-bound LLO conforma- or β-PFTs, based on the secondary structure of their transmem- tions, pore formation, and phospholipid reorganization impli- brane domains (3). Listeriolysin O (LLO), a foodborne pathogen cated in the leakage kinetics. This study has direct bearing on and a cholesterol-dependent cytolysin (CDC) secreted by Lis- our understanding of membrane disruption by pore-forming teria monocytogenes, is implicated in gastroenteritis as well as toxins and lipid-reorganization events known to play an meningitis in immune-compromised individuals (4). Pore forma- important role in signal transduction in cells. tion and membrane rupture provide a unique phagosomal escape strategy, a key role in the survival and growth of L. monocy- Author contributions: K.G.A. and J.K.B. planned and designed research; I.I.P. performed togenes in host cells. Despite their known existence for several the experiments and analysis, R.C. carried out simulations; I.I.P., R.C., K.G.A., and J.K.B. decades, the molecular mechanisms for pore-formation and analyzed data; and I.I.P., R.C., K.G.A., and J.K.B. wrote the paper.y membrane-disruption processes, during PFT-mediated bacterial The authors declare no conflict of interest.y virulence, are still unclear (1). This article is a PNAS Direct Submission.y Understanding the mechanistic pathways for PFTs has relied Published under the PNAS license.y largely on structural data gleaned from cryo-electron microscopy 1 To whom correspondence may be addressed. Email: [email protected] or [email protected] (cryo-EM) and X-ray crystallography, where detergents induce This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. oligomerization to stabilize pore structures (5, 6). Since CDCs 1073/pnas.1821897116/-/DCSupplemental.y and LLO in particular act by binding to membrane cholesterol, www.pnas.org/cgi/doi/10.1073/pnas.1821897116 PNAS Latest Articles j 1 of 6 Downloaded by guest on September 28, 2021 time scales up to a few microseconds, have to a limited extent of LLO. Two distinct populations of GUVs emerged in our been used to illustrate changes in lipid dynamics and confor- observations (Fig. 1). mational transitions in the presence of pore-forming proteins In one population, dye leakage was observed within 3 min of (26–28) as well as antimicrobial peptides (29, 30). However, LLO addition, while in a second population, leakage was not connecting the structure of the membrane-bound oligomeric observed even after a duration of 4 h. We henceforth refer to intermediates to leakage and ensuing lipid reorganization is these disparate populations of leaked and unleaked GUVs as challenging, as it requires simultaneous monitoring of sev- LVs and ULVs, respectively. To rule out the role of intrinsic eral quantities to yield a complete picture of pore-formation composition or size-related heterogeneity of GUVs in leading dynamics. to the observed emergence of two populations of GUVs—LVs In this work, we attempt to bridge this gap and provide a and ULVs—we checked for both labeled lipid and cholesterol microscopic connection between pore formation, lipid dynam- concentration in GUV populations before incorporation of LLO. ics, and leakage indicative of pore function, by using a com- We did not find any intrinsic compositional heterogeneity of sig- bination of FRET and FCS measurements on single GUVs nificance in GUVs, before LLO incubation, which could explain exposed to LLO. Using fluorescently labeled protein and lipids the emergence of LVs or ULVs (SI Appendix, Fig. S2 A–D). In with vesicles containing cyanine dye as a leakage readout, we both LVs and ULVs, the images revealed the presence of labeled correlate different structural states of LLO as revealed by LLO on the membrane (Fig. 1 and SI Appendix, Fig. S3 D and E). FRET, with the changes in lipid diffusivities (FCS) and leak- However, the LVs, on average, showed a higher (approximately age from the GUVs. By using dye leakage as a readout for three times) LLO concentration compared with the ULVs (data pore formation, two distinct populations of GUVs with widely shown in SI Appendix, Fig. S3B). The inherent stochastic nature different leakage kinetics emerge. We attribute these differ- of LLO binding was revealed in the broad distribution of LLO ences to the existence of oligomeric intermediates, sampling concentration on LV or ULV populations. Coupled with the various membrane-bound conformational states of the protein, observation of concentration-dependent lytic activity of LLO on and connect these with concomitant changes in lipid dynam- erythrocytes (SI Appendix, Fig. S1B), our time-lapsed images sug-
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