Biology subjects

Taipale, M.

Publications and source records attributed to Taipale, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Interplay of NuA4/TIP60 and PRC2 Complex Activities in Fusion Driven Endometrial Stromal Sarcoma

Low-grade endometrial stromal sarcoma (LGESS) exhibits frequent chromosomal translocations that fuse various subunits of the NuA4/TIP60 co-activator complex to subunits of the Polycomb Repressive Complex 2 (PRC2) complex. LGESS fusion proteins, such as the commonly occurring JAZF1-SUZ12, have been shown to upregulate genes through mislocalization of NuA4/TIP60 activity to Polycomb target genes. In this study, we characterized an interesting recurrent fusion protein in LGESS that fused a NuA4/TIP60 component, MBTD1, to EZHIP. EZHIP is a recently described vertebrate protein that enzymatically inhibits methyltransferase activity of the PRC2 complex and is a potent oncogene. The MBTD1-EZHIP fusion protein forms a chimeric TIP60-PRC2.1 complex and drastically reduces H3K27me3 levels at Polycomb target genes, similar to EZHIP-overexpressing cancers. However, unlike EZHIP overexpression, MBTD1-EZHIP requires mislocalization of NuA4/TIP60 activity through the MBTD1 protein to upregulate oncogenes. Despite differences in the finer molecular mechanisms, MBTD1-EZHIP and the common JAZF1-SUZ12 fusion protein upregulated similar sets of genes in cell lines, showing a convergence of oncogenic gene expression. Surprisingly, unlike in cellular models, JAZF1-SUZ12 translocated patient samples showed not only upregulation of genes driven by increased H4K8ac and decreased H3K27me3 but also downregulation of specific genes due to accumulated H3K27me3, revealing an additional oncogenic mechanism in LGESS.

cancer biology↗

bioRxiv2026

The Human Bindome: A Proteome-scale Atlas of Designed Binder Candidates

Affinity reagents such as antibodies are indispensable for interrogating proteins biological function. Yet they are costly and frequently unreliable, with unknown sequences, posing challenges to reproducible experimental research. Deep learning-based protein design can now in silico generate affinity reagents achieving reliable experimental success rates, but has remained largely confined to specialist laboratories. Here we present the Human Bindome, a proteome-scale atlas of high-confidence in silico protein binder candidates. By embedding the experimentally benchmarked BindCraft method in an accelerated, parallelized framework with automated domain-level target selection, we generated 306,146 binder candidates covering 8,296 human proteins (40.9% of the full proteome). Every candidate carries a defined sequence, a predicted binder-target structure model, and in silico confidence metrics. We characterize proteome-wide coverage and show that binder epitopes frequently overlap functional sites. This positions the Bindome as a resource of genetically encodable perturbagens for site-specific, modular control of protein function. The Bindome is freely available through a web interface (https://bindome.epfl.ch), with agentic, natural-language querying and as data splits for machine-learning model development. We anticipate that the Bindome will be valuable for the scientific community by providing affinity and perturbation reagents with broad applications in dissecting biological mechanisms as well as in drug and target discovery.

synthetic biology↗

bioRxiv2026

The Nematicide Tioxazafen Disrupts Proteasome Function via Cytochrome P450 Bioactivation

Tioxazafen is an effective nematicide whose commercialization was halted because handlers reportedly developed rashes after working with seeds coated with a tioxazafen-laced cocktail. Here, we show that tioxazafen is bioactivated into toxic products by nematode and human cytochrome P450s. Through systematic analyses, we found that bioactivated tioxazafen disrupts proteasome function, leading to the accumulation of the NRF1 transcription factor ortholog SKN-1A in the nematode C. elegans, and a bounce-back transcriptional up-regulation of proteasome components. Genetic upregulation of the C. elegans proteasome supresses tioxazafens lethality, indicating that proteotoxicity is a key contributor to death. A survey of human P450s revealed that skin-expressed CYP1A1 toxifies tioxazafen and may account for the reaction to tioxazafen-coated seeds. We also found that rabbit CYP1A1 fails to bioactivate tioxazafen, which may explain the pre-market failure to detect robust adverse skin reactions. Our work highlights vulnerabilities in pre-market toxicological assays and a provides potential solution to prospectively identifying P450 toxication events. One-Sentence SummaryTioxazafen is bioactivated by cytochrome P450s into a proteasome disruptor.

pharmacology and toxicology↗

bioRxiv2026

Phosphorylation-driven Targeted Protein Degradation of Oncogenic β-catenin

Therapeutic strategies to inhibit the Wnt signalling pathway for cancer treatment have, so far, failed to advance to the clinic. Induced-proximity drugs are revolutionizing our ability to tackle targets previously considered undruggable. Here, we used an unbiased genome-scale approach to identify induced-proximity protein candidates that inhibit the central Wnt signalling effector {beta}-catenin in colorectal cancer cells. While the identification of several E3 ubiquitin ligases validated our approach, we uncovered that inducing proximity to members of the Casein kinase I (CSNK1) family leads to {beta}-catenin degradation and inhibits the growth of colorectal cancer cells harbouring Wnt pathway mutations. We show that {beta}-catenin degradation induced by CSNK1 proximity is kinase activity- and proteasome-dependent. We propose that the formation of a neo-degron, through kinase recruitment, can expand induced-proximity drug targeting strategies.

molecular biology↗

bioRxiv2025

Systematic Discovery of Pathogen Effector Functions across Human Pathogens and Pathways

Pathogens deploy effector proteins to exploit host cell biology, and most pathogen open reading frames (ORFs) are rapidly evolving and lack functional annotation. We developed the eORFeome, a scalable functional genomics platform encompassing 3,835 effector ORFs from diverse viruses, bacteria, and parasites. High-throughput barcoded screens across NF{kappa}B, apoptosis, p53, cGAS-STING and MHC-I pathways revealed functions for hundreds of uncharacterized eORFs, unexpected new activities for known effectors, and distinct pathway-specific functions encoded by single ORFs. Illustrating the power of the approach, we identify HHV6A U14 as a p53 antagonist, HHV7 U21 as a dual-function STING antagonist and MHC-I antigen display inhibitor, and adenoviral 13.6K/i-leader protein as a de novo evolved TAP inhibitor that suppresses MHC-I display. These results establish a general framework for systematic effector annotation, uncover new mechanisms of host-pathogen interaction across kingdoms, and highlight pathogen effectors as a versatile toolkit for rewiring and probing human cellular pathways.

systems biology↗

bioRxiv2025

Comprehensively Testing the Function of Missense Variation in the STK11 Tumour Suppressor

The tumor suppressor gene STK11 encoding Serine/Threonine Kinase 11 (STK11) is associated with Peutz-Jeghers Syndrome (PJS), a heritable gastrointestinal disease that increases lifetime cancer risk, and with somatic variation that contributes to [~]30% of lung and 20% of cervical cancers. Although identifying pathogenic variants is clinically actionable, over 94% of STK11 missense variants that have been observed clinically lack a definitive classification. We therefore measured the impact of STK11 variants at scale in a mammalian cell-based assay, scoring 6,026 (73% of all possible) amino acid substitutions across the full-length gene. Functional scores--which were consistent with biochemical properties, smaller-scale assays, and pathogenicity annotations--identified a subset of PJS patients with germline STK11 variants diagnosed later in life, as well as somatic STK11 variants found in cancer patients that had comparable overall survival estimates to wild-type STK11. Our scores provided new evidence for 350 annotated VUS STK11 missense variants and [~]80% of missense variants that have not yet been reported clinically, but we might expect to observe in the future. Thus, our effect map provides a proactive resource for gaining sequence-structure-function insights and evidence for actionable interpretation of clinical missense variants.

cancer biology↗

bioRxiv2025

Transcription factor occupancy is affected by genetic variation in the white adipose tissue of C57BL6/j and 129S1/SvImJ mice

Most of the disease associated genetic variants identified in genome wide association studies have been mapped to the non-coding regions of the genome. One of the leading mechanisms by which these variants are thought to affect disease susceptibility is by altering transcription factor (TF) binding. Even though inbred mouse strains have been commonly used to investigate polygenic diseases, less is known on how their genetic differences translate to the level of gene regulation and chromatin landscape. Here, we investigated how genetic variation affects chromatin accessibility, a commonly used proxy for TF binding, and how this relates to gene regulation in the epididymal white adipose tissue (eWAT) of C57BL/6J and 129S1/SvImJ mice fed either chow or high-fat diet. We show that differences in chromatin accessibility are almost exclusively strain-specific and driven by genetic variation. In addition, we integrate ATAC-seq (chromatin accessibility) and H3K27ac ChIP-seq (active regulatory regions) data to show that tissue-specific TFs are commonly found in the active regulatory regions hosting TF binding motif altering variants in eWAT. By incorporating footprint analysis, we also show that TF occupancy is consistent with TF binding motif scores at the genetically altered loci. In addition, we validate these findings by extending the footprint analysis to ATAC-seq and H3K27ac ChIP-seq data obtained from the liver. Also, we employ RNA-seq to show that differentially expressed genes are collocated with differentially accessible regions hosting genetic variants. Overall, our findings highlight the connection between differential chromatin accessibility, TF binding and genetic variation and their role in the gene regulation across metabolically central tissues of a mouse model for polygenic obesity. Author summaryMost of the variants associated with human polygenic disease are outside the protein coding regions of the genome. In this study, we took benefit of the known genetic differences of two inbred mouse strains to investigate the impact of the non-coding genetic variation on the chromatin landscape and the regulation of gene expression in the adipose tissue. Using several complementary sequencing and bioinformatic methods, we show that chromatin accessibility at genetically different transcription factor (TF) binding sites is associated with the strength of the altered TF binding motifs. We also identify the key TFs binding to the regions of genetically determined chromatin accessibility. We further show how the genetic effects propagate to the level of gene expression. Together, these findings give valuable insight into the mechanisms by which genetic variation affects gene regulation and provide future targets for research.

genetics↗

bioRxiv2024

Enhanced delivery of protein therapeutics with a diphtheria toxin-like platform that evades pre-existing neutralizing immunity

Targeted intracellular delivery of therapeutic peptides and proteins remains an important but unresolved goal in biotechnology. A promising approach is to engineer bacterial exotoxins that deliver their cytotoxic enzymes into cells and can be engineered to target cancer cells as is the case with immunotoxins. The well-studied diphtheria toxin translocation domain is ideally suited as a delivery platform as it has been shown to be capable of delivering a wide range of macromolecular cargo. Widespread deployment of DT-based therapeutics in humans, however, is complicated by the prevalence of pre-existing anti-DT antibodies from childhood vaccinations that reduce the exposure, efficacy and safety of this important class of protein drugs. Thus, there is a great need for delivery platforms with no pre-existing immunity in humans. Here, we describe the discovery and characterization of a distant diphtheria toxin homolog from the ancient reptile pathogen Austwickia chelonae that we have named Chelona Toxin (CT). We show that CT is comparable to DT structure and function in all respects except that it is not recognized by pre-existing anti-DT antibodies present in human sera. Moreover, we demonstrate that the CT translocase is superior to the DT translocase at delivering therapeutic protein cargo into target cells. These findings highlight CT as a potentially class-enabling new chassis for developing safer and more efficacious immunotoxins and intracellular protein delivery platforms for cancer therapy.

biochemistry↗

bioRxiv2024

The co-chaperone DNAJA2 buffers proteasomal degradation of cytosolic proteins with missense mutations

Mutations can result in the loss of a proteins native function due to protein misfolding, which is generally handled by an intricate protein quality control network. To better understand the triaging mechanisms of misfolded cytosolic proteins, we screened a human mutation library to identify a panel of unstable mutations. The degradation of these mutated cytosolic proteins is largely dependent on the ubiquitin proteasome system. Using BioID proximity labelling, we found that the co-chaperones DNAJA1 and DNAJA2 are key interactors of one of the mutated proteins. Notably, the absence of DNAJA2 increases the turnover of the mutant protein but not of the wild-type protein. Our work indicates that missense mutations in cytosolic proteins can promote interactions with molecular chaperones that normally do not occur. Assessment of the broader panel of cytosolic mutant proteins shows that the co-chaperone DNAJA2 exhibits three distinct behaviours: acting to stabilize solely the mutant, both the wild-type and mutant proteins, or being dispensable. Our work illustrates how distinct elements of the protein homeostasis network are utilized in the presence of a cytosolic misfolded protein. Summary StatementWe identified a panel of cytosolic mutant proteins degraded by the proteasome. DNAJA2 is often required to prevent mutant protein turnover, even if it is sometimes dispensable for the wild-type protein.

cell biology↗

bioRxiv2023

Pervasive mislocalization of pathogenic coding variants underlying human disorders

Widespread sequencing has yielded thousands of missense variants predicted or confirmed as disease-causing. This creates a new bottleneck: determining the functional impact of each variant - largely a painstaking, customized process undertaken one or a few genes or variants at a time. Here, we established a high-throughput imaging platform to assay the impact of coding variation on protein localization, evaluating 3,547 missense variants of over 1,000 genes and phenotypes. We discovered that mislocalization is a common consequence of coding variation, affecting about one-sixth of all pathogenic missense variants, all cellular compartments, and recessive and dominant disorders alike. Mislocalization is primarily driven by effects on protein stability and membrane insertion rather than disruptions of trafficking signals or specific interactions. Furthermore, mislocalization patterns help explain pleiotropy and disease severity and provide insights on variants of unknown significance. Our publicly available resource will likely accelerate the understanding of coding variation in human diseases.

cell biology↗

bioRxiv2022

Proteome-scale induced proximity screens reveal highly potent protein degraders and stabilizers

Targeted protein degradation and stabilization are promising therapeutic modalities due to their potency and versatility. However, only few E3 ligases and deubiquitinases have been harnessed for this purpose. Moreover, there may be other protein classes that could be exploited for protein stabilization or degradation. Here, we used a proteome-scale platform to identify hundreds of human proteins that can promote the degradation or stabilization of a target protein in a proximity-dependent manner. This allowed us to comprehensively compare the activities of human E3s and deubiquitinases, characterize non-canonical protein degraders and stabilizers, and establish that effectors have vastly different activities against diverse targets. Notably, the top degraders were more potent against multiple therapeutically relevant targets than the currently used E3s CBRN and VHL. Our study provides a functional catalogue of effectors for targeted protein degradation and stabilization and highlights the potential of induced proximity screens for discovery of novel proximity-dependent protein modulators.

molecular biology↗

bioRxiv2022

Accurate simultaneous sequencing of genetic and epigenetic bases in DNA

DNA comprises molecular information stored via genetic bases (G, C, T, A) and also epigenetic bases, principally 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Both genetic and epigenetic information are vital to our understanding of biology and disease states. Most DNA sequencing approaches address either genetics or epigenetics and thus capture incomplete information. Methods widely used to detect epigenetic DNA bases typically fail to capture common C-to-T mutations or distinguish 5mC from 5hmC. Here, we present a single-base-resolution sequencing methodology that will simultaneously sequence complete genetics and complete epigenetics in a single workflow. The approach is non-destructive to DNA and provides a digital readout of bases, which we exemplify by simultaneous sequencing of G, C, T, A, 5mC and 5hmC; 6-Letter sequencing. We demonstrate sequencing of human genomic DNA and also cell-free DNA taken from a blood sample of a cancer patient. The approach is accurate, requires low DNA input and has a simple workflow and analysis pipeline. We envisage it will be versatile across many applications in life sciences.

genomics↗

bioRxiv2022

The kinetic landscape of human transcription factors

Cell-to-cell variability is shaped by transcription dynamics because genes are transcribed in bursts interspersed with inactive periods. The stochasticity of bursting means that genes transcribed in rare bursts exhibit more heterogeneity at the single cell level than genes that burst often 1, 2. Transcription starts with the binding of Transcription Factors (TFs) to specific sequence motifs where they recruit the transcription machinery 3. In some systems, individual TF binding events temporally correlate with the firing of transcriptional bursts, defining the target genes frequency and duration 4-6. However, in the absence of methods that assess the impact of different TFs on transcription dynamics at the same genetic loci, it remains unclear whether DNA binding kinetics are the sole determinant of bursting. Here we develop an imaging-based synthetic recruitment assay, CRISPRburst, and measure how 92 human TFs impact bursting kinetics. We show that TFs recruited to chromatin under identical conditions generate diverse bursting signatures, some TFs increasing the probability of the gene turning on while others increase the number of mRNA molecules transcribed per burst. We find that the association of TFs with specific protein partners determines their bursting output, and train a model to predict the kinetic signatures of all human TFs. These kinetic signatures can be used as a TF classification system complementary to existing families based on DNA binding domains. Additionally, kinetic signatures provide a rational framework to design synthetic activators, model transcription regulation, and understand expression heterogeneity.

biophysics↗

bioRxiv2022

Pharmacological PP2A reactivation overcomes multikinase inhibitor tolerance across brain tumor cell models

BackgroundGlioblastoma is characterized by hyperactivation of kinase signaling pathways. Regardless, most glioblastoma clinical trials targeting kinase signaling have failed. We hypothesized that overcoming the glioblastoma kinase inhibitor tolerance requires efficient shut-down of phosphorylation-dependent signaling rewiring by simultaneous inhibition of multiple critical kinases combined with reactivation of Protein Phosphatase 2A (PP2A). MethodsLive-cell imaging and colony growth assays were used to determine long-term impact of therapy effects on ten brain tumor cell models. Immunoblotting, MS-phosphoproteomics, and Seahorse metabolic assay were used for analysis of therapy-induced signaling rewiring. BH3 profiling was used to understand the mitochondrial apoptosis mechanisms. Medulloblastoma models were used to expand the importance to other brain cancer. Intracranial xenografts were used to validate the in vivo therapeutic impact of the triplet therapy. ResultsCollectively all tested ten glioblastoma and medulloblastoma cell models were effectively eradicated by the newly discovered triplet therapy combining inhibition of AKT and PDK1-4 kinases with pharmacological PP2A reactivation. Mechanistically, the brain tumor cell selective lethality of the triplet therapy could be explained by its combinatorial effects on therapy-induced signaling rewiring, OXPHOS, and apoptosis priming. The brain-penetrant triplet combination had a significant in vivo efficacy in intracranial glioblastoma and medulloblastoma models. ConclusionThe results confirm highly heterogenous responses of brain cancer cells to mono - and doublet combination therapies targeting phosphorylation-dependent signaling. However, the brain cancer cells cannot escape the triplet therapy targeting of AKT, PDK1-4, and PP2A. The results encourage evaluation of brain tumor PP2A status for design of future kinase inhibitor combination trials. Key PointsO_LIDevelopment of triplet kinase-phosphatase targeting therapy strategy for overcoming therapy tolerance across brain tumor models. C_LIO_LIIdentification of interplay between therapy-induced signaling rewiring, OXPHOS, and BH3 protein-mediated apoptosis priming as a cause for kinase inhibitor tolerance in brain cancers. C_LIO_LIValidation of the results in intracranial in vivo models with orally bioavailable and brain penetrant triplet therapy combination. C_LI Importance of the StudyBased on current genetic knowledge, glioblastoma should be particularly suitable target for kinase inhibitor therapies, However, in glioblastoma alone over 180 clinical trials with kinase inhibitors have failed. In this manuscript, we recapitulate this clinical observation by demonstrating broad tolerance of brain cancer cell models to kinase inhibitors even when combined with reactivation of PP2A. However, we discover that the therapy-induced signaling rewiring, and therapy tolerance, can be overcome by triplet targeting of AKT, PDK1-4 and PP2A. We provide strong evidence for the translatability of the findings by orally dosed brain penetrant triplet therapy combination in intracranial brain cancer models. The results encourage biomarker profiling of brain tumors for their PP2A status for clinical trials with combination of AKT and PDK1-4 inhibitors. Further, the results indicate that rapidly developing PP2A reactivation therapies will constitute an attractive future therapy option for brain tumors when combined with multi-kinase inhibition.

cancer biology↗

bioRxiv2022

Triplet kinase-phosphatase targeting to overcome kinase inhibitor tolerance in brain tumor cells

Therapeutic resistance to kinase inhibitors constitutes a major unresolved clinical challenge in cancer and especially in glioblastoma. Multi-kinase inhibitors may be used for simultaneous targeting of multiple target kinase and thereby potentially overcome kinase inhibitor resistance. However, in most cases identification of the target kinases mediating therapeutic effects of multi-kinase inhibitors has been challenging. To tackle this important problem, we developed an Actionable Targets of Multi-kinase Inhibitors (AToMI) strategy and used it for characterization of glioblastoma target kinases of staurosporine derivatives displaying synergy with protein phosphatase 2A (PP2A) reactivation. AToMI consists of interchangeable modules combining drug-kinase interaction assay, siRNA high-throughput screening, bioinformatics analysis and validation screening with more selective target kinase inhibitors. As a result, AToMI analysis revealed AKT and mitochondrial pyruvate dehydrogenase kinase PDK1 and PDK4 as kinase targets of staurosporine derivatives UCN-01, CEP-701, and K252a that synergized with PP2A activation across heterogeneous glioblastoma cells. Based on these proof-of-principle results we propose that application and further development of AToMI for clinically applicable multi-kinase inhibitors could provide significant benefits in overcoming the challenge of lack of knowledge of target specificity of multi-kinase inhibitors.

cancer biology↗

bioRxiv2021

Identification and functional characterization of transcriptional activators in human cells

Transcription is orchestrated by thousands of transcription factors and chromatin-associated proteins, but how these are causally connected to transcriptional activation or repression is poorly understood. Here, we conduct an unbiased proteome-scale screen to systematically uncover human proteins that activate transcription in a natural chromatin context. We also identify potent transactivation domains among the hits. By combining interaction proteomics and chemical inhibitors, we delineate the preference of both known and novel transcriptional activators for specific co-activators, highlighting how even closely related TFs can function via distinct co-factors. Finally, we show that many novel activators are partners in fusion events in tumors and functionally characterize a myofibroma-associated fusion between SRF and C3orf62, a potent activator. SRF-C3orf62 activates transcription in a CBP/p300-dependent manner and promotes proliferative and myogenic transcriptional programs. Our work provides a functional catalogue of potent transactivators in the human proteome and a platform for discovering transcriptional regulators at genome scale.

molecular biology↗

bioRxiv2021

Recurrent chromosomal translocations in sarcomas create a mega-complex that mislocalizes NuA4/TIP60 to Polycomb target loci

Chromosomal translocations frequently promote carcinogenesis by producing gain-of-function fusion proteins. Recent studies have identified highly recurrent chromosomal translocations in patients with Endometrial Stromal Sarcomas (ESS) and Ossifying FibroMyxoid Tumors (OFMT) leading to an in-frame fusion of PHF1 (PCL1) to six different subunits of the NuA4/TIP60 complex. While NuA4/TIP60 is a co-activator that acetylates chromatin and loads the H2A.Z histone variant, PHF1 is part of the Polycomb repressive complex 2 (PRC2) linked to transcriptional repression of key developmental genes through methylation of histone H3 on lysine 27. In this study, we characterize the fusion protein produced by the EPC1-PHF1 translocation. The chimeric protein assembles a mega-complex harboring both NuA4/TIP60 and PRC2 activities and leads to mislocalization of chromatin marks in the genome, in particular over an entire topologically- associating domain including part of the HOXD cluster. This is linked to aberrant gene expression, most notably increased expression of PRC2 target genes. Furthermore, we show that JAZF1, implicated with a PRC2 component in the most frequent translocation in ESS, JAZF1-SUZ12, is a potent transcription activator that physically associates with NuA4/TIP60, its fusion creating similar outcomes as EPC1-PHF1. Importantly, the specific increased expression of PRC2 targets/HOX genes was also confirmed with ESS patient samples. Altogether, these results indicate that most chromosomal translocations linked to these sarcomas employ the same molecular oncogenic mechanism through a physical merge of NuA4/TIP60 and PRC2 complexes leading to mislocalization of histone marks and aberrant polycomb target gene expression.

molecular biology↗

bioRxiv2019

Identification of the C. sordellii lethal toxin receptor elucidates principles of receptor specificity in clostridial toxins

Clostridium sordellii lethal toxin (TcsL) is responsible for an almost invariably lethal toxic shock syndrome associated with gynecological C. sordellii infections. Here, using CRISPR/Cas9 screening, we identify semaphorins SEMA6A and SEMA6B as the cellular receptors for TcsL and demonstrate that soluble extracellular SEMA6A can protect mice from TcsL-induced edema. A 3.3 [A] cryo-EM structure shows that TcsL binds SEMA6A with the same region that the highly related C. difficile TcdB toxin uses to bind structurally unrelated Frizzled receptors. Remarkably, reciprocal mutations in this evolutionarily divergent surface are sufficient to switch receptor specificity between the toxins. Our findings establish semaphorins as physiologically relevant receptors for TcsL, and reveal the molecular basis for the difference in tissue targeting and disease pathogenesis between highly related toxins.

molecular biology↗