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Biology subjects

Taylor, N. M. I.

Publications and source records attributed to Taylor, N. M. I..

At least 19 recordsLinked to original sources

Piercing mechanism in the minimal contractile tail of bacteriophage P2.

Bacteriophage P2 is a long-standing model for contractile injection systems, yet high-resolution structures of the intact virion and the mechanism of baseplate activation have remained unresolved. Here, we combine high-resolution cryo-electron microscopy and in situ cryo-electron tomography to characterize P2, using its lytic mutant P2vir, in its pre- and post-contraction states and during host infection. We identify a previously undescribed fold in the head-to-tail adaptor, which mediates the transition from 12-fold portal symmetry to sixfold tail symmetry through interlocking {beta}-strand handshake interactions. Our structures further reveal a compact, threefold-symmetric baseplate established by a distinctive loop-helix module formed by the hub and tube initiator, which bioinformatic and phylogenetic analyses identify as a characteristic architectural feature of the Peduovirus lineage. We also propose a rope-like arrangement that anchors the tail fibre to the baseplate triplex component gpI and obtain evidence that the tape-measure protein adopts a C3 arrangement within the tail lumen, while computational predictions suggest a possible hexameric, pore-like organization after release. Comparison of pre- and post-contraction particles, supported by in situ imaging of infection, suggests that sheath contraction destabilizes the baseplate, promoting its disassembly. The inner tail tube appears to penetrate the host outer membrane but does not appear to reach the inner membrane, leading us to propose that the reorganized tape-measure protein forms a secondary conduit for genome translocation. These findings support a distinct model of contractile tail activation and expand the known architectural diversity of viral injection systems.

microbiology↗

Structural modularity of receptor-binding proteins underlies host-range strategy diversification in Klebsiella pneumoniae phages

Bacteriophage receptor-binding proteins (RBPs) determine bacterial host recognition and are central to phage host-range evolution, yet the structural principles governing how RBPs diversify and expand host range remain not fully understood. Although phage RBPs are thought to evolve through modular exchange of receptor-binding domains, it is unclear how this modularity is organised across diverse RBP architectures, at what structural scales recombination operates, and how it shapes host-range breadth. Here we combined large-scale AlphaFold3 structural modelling, domain-level annotation, de novo pseudo-domain segmentation, sequence modularity analysis and experimentally determined host-range phenotypes across 192 Klebsiella pneumoniae phages and 382 high-confidence RBPs spanning up to 96 K-types. We generated the first system-wide structural atlas of K. pneumoniae phage RBPs, resolving 39 structurally distinct RBP-classes. Although capsule-degrading beta-helix depolymerases dominated numerically, 161 RBPs across 37 RBP-classes employed non-depolymerase architectures, including 18 novel RBP-classes. Structural and sequence analyses show that this diversity arose through modular reuse of structural domains rather than independent invention. Conserved N-terminal scaffolds linked depolymerase and non-depolymerase RBPs across morphotypes, while receptor-binding regions diversified through recombination operating at and beyond domain boundaries. We found recent modular exchange both within genera, where capsule-specific and capsule-independent RBPs can be swapped to alter host-range strategy, and across morphotypes, where depolymerase modules moved between distant lineages altering capsule specificity. Together, these architectures resolve into six receptor-recognition strategies, establishing multi-scale modularity as the primary organising principle of RBP diversification and a structure-informed framework for guiding phage isolation and engineering against K. pneumoniae. The complete atlas is freely accessible as an interactive community resource at Klebsiella-Phage-RBP-Atlas.

evolutionary biology↗

Molecular basis of the Druantia anti-phage defense system

Eukaryotes and prokaryotes have evolved diverse antiviral immune systems, many containing helicase modules central to defense. Druantia are widespread bacterial anti-phage defense systems, each built around a large helicase domain-containing protein, DruE, paired with variable subunits. Here, we investigate the molecular basis of a minimal two-protein module Druantia system, DruH-E. We demonstrate that DruH-E is sufficient to confer robust anti-phage defense. DruE exists in equilibrium between a monomer and an asymmetric dimer, with dimerization required for in vivo immunity. Cryo-EM structures define DruE asymmetric dimer assembly and its dsDNA unwinding mechanism, revealing a topologically closed architecture that is specifically activated by dsDNA substrates with a 3' overhang. We further identify DruH as an ssDNA-binding protein regulated by a metabolic switch, where its activity is inhibited by ATP at physiological concentrations through direct competition with ssDNA. Supported by mass spectrometry and single-cell microscopy data, we establish key determinants of the Druantia defense system and reveal how it mediates a direct antiviral immune mechanism.

microbiology↗

Genome delivery of a contractile tailed phage and its superinfection exclusion mechanism

Successful viral infection requires efficient adsorption to the target cell, followed by membrane penetration for genome translocation into the host cytoplasm. Bacteriophage T4 initiates infection by binding to Escherichia coli receptors, triggering sequential conformational changes that culminate in genome delivery through viral channels spanning the host cell envelope. Here, we resolved structures of bacteriophage T4 at discrete stages. This revealed how long tail fiber extension affects the baseplate to initiate tail contraction, and the channel formation by the tape measure protein for genome translocation. We further demonstrate that the virus-encoded superinfection exclusion protein Imm binds to the tape measure protein to prevent secondary infections. Our findings offer insights into the coordinated process of genome delivery and phage-encoded superinfection exclusion proteins that prevent genome translocation.

microbiology↗

Structure of a novel contractile injection system in subsp.

Extracellular contractile injection systems (eCISs) are phage-derived nanomachines used by bacteria to deliver effectors into target cells. Well-studied examples include the Photorhabdus asymbiotica virulence cassettes and the antifeeding prophage from Serratia entomophila, which have been engineered for heterologous cargo delivery. Recent genomic analyses identified previously uncharacterized eCIS gene clusters in the opportunistic human pathogen Salmonella enterica subspecies salamae, but their structure, function, and biotechnological potential remain unexplored. Here, we report a high-resolution cryo-electron microscopy structure of the S. enterica eCIS. Our atomic models reveal a unique sheath architecture, an expansive cage-like shell around a central spike, and an associated transmembrane hydrolase. We identify a putative effector encoded within the operon exhibiting periplasmic toxicity and provide evidence that the S. enterica eCIS deviates from canonical eCISs by interacting with the inner membrane. Guided by these structural features, we uncover a previously unannotated cluster of contractile injection systems (CISs). Together, our findings expand the known diversity of CISs structures and functions and lay the groundwork for engineering customizable protein delivery platforms.

microbiology↗

Structural characterization of an extracellular contractile injection system from Photorhabdus luminescens in extended and contracted states.

Contractile injection systems (CISs) are phage-tail-like nanosyringes that mediate bacterial interactions by puncturing target cell membranes. Within these systems, Photorhabdus Virulence Cassettes (PVCs) can translocate toxins across eukaryotic target cell membranes. The structure of a PVC has been described at atomic level and engineered to deliver diverse protein cargoes into non-natively-targeted organisms. Despite the structural insights into several CISs, information on PVCs from other species and details on the contraction mechanism remain limited. Here, we present the single-particle cryo-electron microscopy structure of PlPVC1, a PVC from the nematode symbiont and insect pathogen Photorhabdus luminescens DJC, in both extended and contracted states. Our structure displays distinct structural features that differ from other CISs, such as a cage surrounding the central spike, a larger sheath adaptor, and a plug exposed to the tube lumen. Moreover, we present the structures of the PlPVC1 fiber as well as the baseplate of the contracted particle, yielding insight into the contraction mechanism. This study provides structural details of the contracted state of the PlPVC1 particle and supports the model in which contraction is triggered. Furthermore, it facilitates the comparison of PlPVC1 with other contractile systems and expands the scope of engineering opportunities for future biomedical and biotechnological applications.

molecular biology↗

Role of N-glycosylation as a determinant of ATG9A conformations and activity

In this study we investigate the effects of glycosylation at position N99 on the structural dynamics and lipid scrambling activity of ATG9A, a key autophagy protein, using microsecond all-atom molecular dynamics (MD) simulations. ATG9A is an integral membrane protein involved in autophagosome biogenesis, and glycosylation at N99 is known to play a critical, yet poorly understood role in its function. The MD simulations revealed that the hydrophilic central cavity of ATG9A supports lipid reorientation and partial transbilayer movements, consistent with its lipid scrambling activity observed experimentally. N-glycosylation at N99 was found to enhance cooperative interactions between protomers, facilitating lipid insertion and traversal within the central cavity. These findings align with the proposed mechanism of ATG9A role in lipid redistribution across the phagophore membrane during autophagy. However, mutagenesis experiments that abolish N-glycosylation in ATG9A (ATG9AN99A and ATG9AN99D mutants) did not show a significant change in autophagy flux, suggesting that further experimental approaches, such as lipid scramblase assays, are needed to pinpoint the function of glycosylation. In this study we also observed an asymmetric protomer conformations in ATG9A, contrasting with symmetric structures obtained from cryo-EM, suggesting that the structural heterogeneity of the protein could be further explored in cryo-EM datasets. Overall, the study highlights the importance of incorporating glycosylation in computational studies of membrane proteins and offers valuable insights into the molecular mechanisms of lipid transport in autophagy, with potential implications for other lipid scramblases and flippases.

biophysics↗

Towards a complete phage tail fiber structure atlas.

Bacteriophages use receptor-binding proteins (RBPs) to adhere to bacterial hosts. Understanding the structure of these RBPs can provide insights into their target interactions. Tail fibers, a prominent type of RBP, are typically elongated, flexible, and trimeric proteins, making it challenging to obtain high-resolution experimental data of their full-length structures. Recent advancements in deep learning-based protein structure prediction, such as AlphaFold2-multimer (AF2M) and ESMfold, allow for the generation of high-confidence predicted models of complete tail fibers. In this paper, we introduce RBPseg, a method that combines monomeric ESMfold predictions with a novel sigmoid distance pair (sDp) protein segmentation technique. This method segments the tail fiber sequences into smaller fractions, preserving domain boundaries. These segments are then predicted in parallel using AF2M and assembled into a full fiber model. We demonstrate that RBPseg significantly improves AF2M v2.3.2 in terms of model confidence, running time, and memory usage. To validate our approach, we used single-particle cryo-electron microscopy to analyze five tail fibers from three phages of the BASEL collection. Additionally, we conducted a structural classification of 67 fibers and their domains, which identified 16 well-defined tail fiber classes and 89 domains. Our findings suggest the existence of modular fibers as well as fibers with different sequences and shared structure, indicating possible sequence convergence, divergence, and domain swapping. We further demonstrate that these structural classes account for at least 24% of the known tail fiber universe.

microbiology↗

T6SS-associated Rhs toxin containers: Structural and functional insights into bacterial weaponry and self-protection

Bacteria use the type VI secretion system (T6SS) to secrete a variety of toxins into pro- and eukaryotic cells via a machinery consisting of a contractile sheath and a rigid tube. Rearrangement hotspot (Rhs) proteins represent one of the most common T6SS-secreted effectors. The C-terminal toxin domain of Rhs proteins displays great functional diversity, while the large Rhs core is characterised by YD repeats. T6SS- associated Rhs proteins are attached to the VgrG spike protein, often via an N- terminal PAAR-repeat domain. Using X-ray crystallography, we here elucidate the Rhs core structures of PAAR- and VgrG-linked Rhs proteins from Salmonella bongori and Advenella mimigardefordensis, respectively. The Rhs core forms a large container made up of {beta}-sheets that has a negatively charged interior and encloses a large volume. The presence of the toxin domain of S. bongori PAAR-linked Rhs does not lead to ordered density in the Rhs container, suggesting the toxin domain is at least partially unfolded. Together with bioinformatics analysis showing that Rhs toxins predominantly act intracellularly, this suggests that the Rhs core domain functions two-fold, as safety feature for the producer cell and as delivery mechanism for the toxin domain. Our results strengthen our knowledge of Rhs structure and function.

biochemistry↗

Structure and mechanism of Zorya anti-phage defense system

Zorya is a recently identified and widely distributed bacterial immune system, which protects against phage invasion. It consists of a predicted membrane-embedded complex (ZorAB) and soluble components that differ among Zorya subtypes, notably ZorC and ZorD, in type I Zorya systems. Here, we reveal the molecular basis of the Zorya defense system using cryo-electron microscopy, mutagenesis, fluorescence microscopy, proteomics, and functional studies. We demonstrate that ZorAB shares the stoichiometry of other 5:2 inner membrane ion-driven rotary motors. Additionally, ZorA5B2 features a dimeric ZorB peptidoglycan binding domain and a pentameric -helical coiled-coil tail made of ZorA that projects approximately 700 [A] into the cytoplasm. We further characterize the structure and function of the soluble Zorya components, ZorC and ZorD, and find that they harbour DNA binding and nuclease activity, respectively. Comprehensive functional and mutational analyses demonstrates that all Zorya components work in concert to protect bacterial cells against invading phages. We present evidence that ZorAB operates as an ion-driven motor that becomes activated and anchors to the cell wall upon sensing of cell envelope perturbations during phage invasion. Subsequently, ZorAB transfers the phage invasion signal through the ZorA cytoplasmic tail to the soluble effectors, which function to prevent phage propagation. In summary, our study elucidates the foundational mechanisms of Zorya function and reveals a novel triggering signal for the rapid activation of an anti-phage defense system.

molecular biology↗

N-terminal toxin signal peptides efficiently load therapeutics into a natural nano-injection system

Targeted delivery of therapeutics to specific cells is a major bottleneck towards personalized medicine. The extracellular injection system (eCIS) of Serratia entomophila, the antifeeding prophage (Afp), promises potential for drug delivery purposes. However, the precise mechanism of action, toxin location, and Afp loading remain unclear. Here, we reveal a minimal N-terminal signal peptide (NtSP) of the toxin Afp18, that plays a key role in toxin packing. By engineering fusion proteins, we demonstrate that Afp18s NtSP can shuttle effectors for Afp loading. We packed non-eCIS effectors, including CRISPR-Cas protein Cas{Phi}-2 from Biggiephage, and a human antimicrobial peptide, LL37, into Afp. Additionally, NtSPs from eCIS effectors of other species facilitate loading of Cas{Phi}-2 into Afp. We observed cargo being packed inside the Afp tail tube through cryo-EM single particle analysis. The presented results enhance our understanding of eCIS toxin packing and contribute to their development as targeted delivery systems. TeaserA novel use of the Afp nano injection systems N-terminal signal peptide in targeted therapeutics delivery

molecular biology↗

Agtrevirus phage AV101 infect diverse extended spectrum β-lactamase E. coli by recognizing four different O-antigens

Bacteriophages in the Agtrevirus genus are known for expressing multiple tail spike proteins (TSPs), but little is known about their genetic diversity and host recognition apart from their ability to infect diverse Enterobacteriaceae species. Here we aim to determine the genetic differences that may account for the diverse host ranges of Agrevirus phages. We performed comparative genomics of 14 Agtrevirus and identified only a few genetic differences including genes involved in nucleotide metabolism. Most notably was the diversity of the tsp gene cluster, specifically in the receptor binding domains that were unique among most of the phages. We further characterized agtrevirus AV101 infecting nine diverse Extended Spectrum {beta}-lactamase (ESBL) E. coli and demonstrated that this phage encoded four unique TSPs among Agtrevirus. Purified TSPs formed translucent zones and inhibited AV101 infection of specific hosts, demonstrating that TSP1, TSP2, TSP3, and TSP4 recognize O8, O82, O153, and O159 O-antigens of ESBL E. coli, respectively. BLASTp analysis showed that the receptor binding domain of TSP1, TSP2, TSP3 and TSP4 are similar to TSPs encoded by E. coli prophages and distant related virulent phages. Thus, Agtrevirus may have gained their receptor binding domains by recombining with prophages or virulent phages. Overall, combining bioinformatic and biological data expands the understanding of TSP host recognition of Agtrevirus and give new insight into the origin and acquisition of receptor binding domains of Ackermannviridae phages. One sentence summaryAgtrevirus phage AV101 express four unique tail spike proteins that recognize different O-antigens of Extended Spectrum {beta}-Lactamase producing E. coli.

microbiology↗

Structural and Mechanistic Basis of Substrate Transport by the Multidrug Transporter MRP4

Multidrug resistance-associated protein 4 (MRP4) is an ATP-binding cassette (ABC) transporter expressed at multiple tissue barriers where it actively extrudes a wide variety of drug compounds. Overexpression of MRP4 provides resistance to clinically used antineoplastic and antiviral agents, making it a highly attractive therapeutic target for countering multidrug resistance. Here we report the cryo-EM structures of multiple physiologically relevant states of membrane-embedded human MRP4, including complexes between MRP4 and two widely used chemotherapeutic agents and a complex between MRP4 and its native substrate. The structures display clear similarities and distinct differences in the coordination of these chemically diverse substrates and, in combination with functional and mutational analysis, reveal molecular details of the transport mechanism. Our study provides key insights regarding the basis of the unusually broad substrate specificity of MRP4 and constitutes an important contribution towards a general understanding of the versatile ensemble of multidrug transporters.

molecular biology↗

Mechanisms of ion selectivity and rotor coupling in the bacterial flagellar sodium-driven stator unit

Bacteria swim using a flagellar motor that is powered by stator units. These stator units are energized by an ionic gradient across the membrane, typically proton or sodium. The presumed monodirectional rotation of the stator units allows the bidirectional rotation of the flagellar motor. However, how ion selectivity is attained, how ion transport triggers the directional rotation of the stator unit, and how the stator unit is incorporated into the motor remain largely unclear. Here we have determined by cryo-electron microscopy the structure of the Na+-driven type stator unit PomAB from the gram-negative bacterium Vibrio alginolyticus in both lipidic and detergent environments, at a resolution up to 2.5 [A]. The structure is in a plugged, auto-inhibited state consisting of five PomA subunits surrounding two PomB subunits. The electrostatic potential map uncovers sodium ion binding sites within the transmembrane domain, which together with functional experiments and explicit solvent molecular dynamics simulations, suggest a mechanism for ion translocation and selectivity. Resolved conformational isomers of bulky hydrophobic residues from PomA, in the vicinity of key determinant residues for sodium ion coupling of PomB, prime PomA for clockwise rotation. The rotation is tightly blocked by the trans-mode organization of the PomB plug motifs. The structure also reveals a conformationally dynamic helical motif at the C-terminus of PomA, which we propose regulates the distance between PomA subunit cytoplasmic domains and is involved in stator unit-rotor interaction, concomitant stator unit activation, and torque transmission. Together, our studies provide mechanistic insight for understanding flagellar stator unit ion selectivity and incorporation of the stator units into the motor.

microbiology↗

Cryo-EM structure of native human thyroglobulin

The thyroglobulin (Tg) protein is essential to thyroid hormone synthesis, playing a vital role in the regulation of metabolism, development and growth. Its structure is conserved among vertebrates. Tg is delivered through the secretory pathway of the thyroid follicular unit to the central colloid depository, where it is iodinated at specific tyrosine sites to form mono- or diiodotyrosine, which combine to produce triiodothyronine (T3) and thyroxine (T4), respectively. Synthesis of these hormones depends on the precise 3D structure of Tg, which has remained unknown despite decades of research. Here, we present the cryo-electron microscopy structure of human thyroglobulin (hTg) to a global resolution of 3.2 [A]. The structure provides detailed information on the location of the hTg hormonogenic sites and reveals the position as well as the role of many of its glycosylation sites. Our results offer structural insight into thyroid hormonogenesis and provide a fundamental understanding of clinically relevant hTg mutations, which can improve treatment of thyroid diseases.

biophysics↗

Molecular basis for recognition of Listeria cell wall teichoic acid by the pseudo-symmetric SH3b-like repeats of a bacteriophage endolysin

Endolysins are bacteriophage-encoded peptidoglycan hydrolases targeting the cell wall of host bacteria via their cell wall-binding domains (CBDs). The molecular basis for selective recognition of surface carbohydrate ligands by CBDs remains elusive. Here, we describe, in atomic detail, the interaction between the Listeria phage endolysin domain CBD500 and its cell wall teichoic acid (WTA) ligands. We show that 3 O-acetylated GlcNAc residues integrated into the WTA polymer chain are the key epitope recognized by a CBD binding cavity located at the interface of tandem copies of beta-barrel, pseudo-symmetric SH3b-like repeats. This cavity consists of multiple aromatic residues making extensive interactions with two GlcNAc acetyl groups via hydrogen bonds and van der Waals contacts, while permitting the docking of the diastereomorphic ligands. The multidisciplinary approach described here delineates a previously unknown recognition mechanism by which a phage endolysin specifically recognizes and targets WTA, suggesting an adaptable model for regulation of endolysin specificity.

biophysics↗

Structure and function of stator units of the bacterial flagellar motor

Many bacteria use the flagellum for locomotion and chemotaxis. Its bi-directional rotation is driven by the membrane-embedded motor, which uses energy from the transmembrane ion gradient to generate torque at the interface between stator units and rotor. The structural organization of the stator unit (MotAB), its conformational changes upon ion transport and how these changes power rotation of the flagellum, remain unknown. Here we present ~3 [A]-resolution cryo-electron microscopy reconstructions of the stator unit in different functional states. We show that the stator unit consists of a dimer of MotB surrounded by a pentamer of MotA. Combining structural data with mutagenesis and functional studies, we identify key residues involved in torque generation and present a mechanistic model for motor function and switching of rotational direction. One Sentence SummaryStructural basis of torque generation in the bidirectional bacterial flagellar motor

biophysics↗

Gain-of-function mutations amplify cytotoxic FAM111 protease activity in human genetic disorders

Dominant missense mutations in the human serine protease FAM111A underlie perinatally lethal gracile bone dysplasia and Kenny-Caffey syndrome 1-3, yet how FAM111A mutations lead to disease is not known. We show that FAM111A proteolytic activity suppresses DNA replication and transcription by displacing key effectors of these processes from chromatin, triggering rapid programmed cell death by Caspase-dependent apoptosis to potently undermine cell viability. Patient-associated point mutations in FAM111A exacerbate these phenotypes by hyperactivating its intrinsic protease activity. Moreover, FAM111A forms a complex with the uncharacterized homologous serine protease FAM111B, point mutations in which cause a hereditary fibrosing poikiloderma syndrome 4, and we demonstrate that disease-associated FAM111B mutants display amplified proteolytic activity and phenocopy the cellular impact of deregulated FAM111A catalytic activity. Thus, patient-associated FAM111A and FAM111B mutations may drive multisystem disorders via a common gain-of-function mechanism that relieves inhibitory constraints on their protease activities to powerfully undermine cellular fitness.

cell biology↗