Biology subjects

Wells, J. A.

Publications and source records attributed to Wells, J. A..

At least 19 recordsLinked to original sources

bioRxiv2026

Structural and mechanistic analyses reveal collaborative regulation of HSF1 by the Hsp70-Hsp90 chaperone systems

Heat shock factor 1 (HSF1) is the master transcriptional regulator of cellular response to disrupted cytosolic protein homeostasis. Temperature change, oxidation, and other stresses drive the trimerization and activation of HSF1 to induce expression of molecular chaperones, such as heat shock proteins Hsp70 and Hsp90, which sit at the center of cellular proteostatic networks. In turn, the HSPs and co-chaperones regulate HSF1, but mechanistic details of this cycle remain largely unknown. We developed a FRET-based approach to simultaneously monitor HSF1 conformational change and oligomeric state throughout activation and inactivation. By reconstituting Hsp-HSF1 interactions in vitro, we find that monomerization of HSF1 resembles fibril disassembly through coordinated Hsp40-Hsp70 activity. We then used site-specific photocrosslinking to track HSF1 loading into Hsp90 complexes, Hsp90 cycling, and stress-induced shifts in Hsp90-HSF1 interactions. Whereas Hsp90 inhibitors force 'loading state' type Hsp90-HSF1 interactions, heat shock promotes faster Hsp90 cycling. In this reconstituted system, HSF1-Hsp90 interactions are unexpectedly strongly dependent on the co-chaperone HOP, in contrast to canonical Hsp90 clients. Combining cryo-EM structures of Hsp90-HSF1 loading state and maturation state complexes with crosslinking mass spectroscopy and biophysical experiments, we show that Hsp90 holds HSF1 in a pre-activated, extended monomer state that is primed for trimerization. We propose this state both enhances responsivity but also promotes cytoplasmic-nuclear shuttling through exposure of the NLS. Notably, Hsp90-bound HSF1 can trimerize and bind DNA, placing it on-pathway for transcriptional activation. Together, our results unify previously contradictory view on Hsp90's role in HSF1 regulation. The integrated combination of in vitro reconstitution, photocrosslinking, cryoEM and MS is an exciting new paradigm for the study of many dynamic systems including other complex proteostasis components.

biochemistry↗

bioRxiv2026

A de novo designed enzyme for photo-proximity labeling of E3 ligase neighborhoods in live cells

Photocatalytic proximity labeling proteomics (photo-PLP) has emerged as a powerful technology for rapid capture of protein interactomes in situ. Typically, photo-PLP relies on chemical conjugation of the photocatalyst to the target of interest which creates practical challenges for derivatized photocatalyst synthesis and bioconjugation specificity. Integrating the precision of genetically encodable enzymes with the versatility of chemically defined photocatalysts provides a modular approach to further expand the scope of neighborhood mapping. Here, we present EYClamp, a de novo designed proximity labeling enzyme harnessing the off-the-shelf photocatalyst Eosin Y (EY) as a cofactor. Using a domain-swapped dimer architecture, we designed a scaffold that binds EY with high affinity (Kd = 10 nM) and lengthens its triplet excited-state lifetime by 29-fold. EYClamp enables efficient, multi-scale photocatalytic proximity labeling in live cells with aryl-diazirine-, aryl-azide- and phenol-biotin. We genetically fused EYClamp to a panel of six important E3 ligases. Using EYClamp, we identified over 1,500 candidate neighbors for KEAP1, MDM2, ASB7 and STUB1, providing a broad and unbiased view of these important neighborhoods. Critical functional networks were revealed including ASB7 engagement with HP1a/CUL5 complex for heterochromatin remodeling. Our EYClamp provides a genetically encodable "plug-and-play" solution for photo-PLP interactome discovery of the large family of E3 ligases and establishes domain-swapping as a promising strategy for de novo photoenzyme design.

biochemistry↗

bioRxiv2026

Extending structural surfaceomics to identify aberrant conformations of tumor surface proteins as potential immunotherapy targets

The complement of tumor cell surface proteins, or "surfaceome", is a rich source of potential immunotherapy targets. To move beyond expression-based target discovery, we previously described "structural surfaceomics," combining crosslinking mass spectrometry (XL-MS) with surface protein biotinylation to identify conformation-selective targets. In our prior work, we applied this method to a single model of acute myeloid leukemia (AML), identifying active integrin beta-2 as a promising target. Here, we expand structural surfaceomics to identify additional immunotherapy targets and surface protein biology across additional models of AML, multiple myeloma, and prostate cancer, as well as donor peripheral blood mononuclear cells. Utilizing these models and different chemical crosslinkers, we compile an extensive database of 5,209 crosslinks. We characterize both shared and unique crosslink-based features, identifying 1,612 disease model-specific crosslinks, including 212 potentially defining tumor-specific conformations based on distance constraint violations relative to AlphaFold predictions. We further implement a suite of emerging modeling tools to predict tumor-specific protein structures. We probe crosslinking patterns suggesting multiple myeloma-specific CD48 and AML-specific integrin 1/{beta}4 heterodimer conformations. This work establishes a resource for cancer structural biology by implementation of structural surfaceomics. Our findings also point toward more realistic protein design models, potentially enabling systematic detection of targetable cancer-specific epitopes for next-generation immunotherapies.

cancer biology↗

bioRxiv2026

Targeted extracellular degradation of LRP8 promotes ferroptosis in cancer cells

Tumor reliance on antioxidant defenses creates a vulnerability to ferroptosis, yet strategies to therapeutically disable these systems remain limited. Here, we identify targeted degradation of the selenium uptake receptor LRP8 as an effective approach to decrease the abundance of the ferroptosis-protective enzyme glutathione peroxidase 4 (GPX4). Using bispecific cytokine receptor-targeting chimeras (KineTACs) that couple LRP8 to cytokine receptor internalization pathways, we selectively direct LRP8 to the lysosome for degradation. LRP8 degradation reduces the abundance of several selenoproteins, including GPX4, lowering the cellular threshold for lipid peroxidation and sensitizing cancer cells to ferroptosis. These findings establish receptor-mediated selenium uptake as a critical, targetable node in ferroptosis resistance and demonstrate that extracellular protein degradation can be leveraged to reprogram intracellular translational dependencies in cancer cells. More broadly, this work provides a framework for exploiting nutrient acquisition pathways to overcome therapy resistance.

bioengineering↗

bioRxiv2026

Targeted shedding of extracellular membrane proteins by induced protease recruitment

Extracellular targeted protein degradation has emerged as a promising therapeutic modality to eliminate proteins of interest (POIs) at the cell surface, by using bifunctional molecules to recruit natural recycling receptors or membrane-bound E3 ligases that redirect POIs to the lysosome. Another natural mechanism involves extracellular proteases that cleave and shed extracellular domains. Here, we exploit this endogenous mechanism by engineering bispecific antibody Shedders, that recruit a classic sheddase ADAM10 to POIs, inducing selective ectodomain shedding. We first targeted the immune checkpoint receptor LAG-3 and observed robust depletion of surface LAG-3 accompanied by accumulation of soluble LAG-3 fragments in both engineered cell lines and primary human T cells. Using biochemical and imaging assays, we confirmed that this antibody-induced shedding is restricted to extracellular protease activity and occurs independently of lysosomal trafficking. Notably, induced shedding of LAG-3 on activated primary T cells partially alleviated inhibitory signaling and reinvigorated IFN{gamma} secretion. We extended the scope of induced shedding by developing Shedders that recognize synthetic epitope-tags that enabling rapid assessment of substrate compatibility across diverse targets. Using this platform, we identified multiple immune modulatory cell-surface receptors, including IL6R, CD62L and MIC-A that can be targeted for shedding. In summary, this work establishes a new paradigm for targeted extracellular proteolysis and expands the toolkit for studying extracellular proteolysis with potential therapeutic benefit.

bioengineering↗

bioRxiv2026

Cellular consequences, citrullination substrates, and antigenicity resulting from wild-type and targeted PAD4 on cell surfaces

Protein arginine deiminase-4 (PAD4) catalyzes hydrolysis of arginine to citrulline in proteins that promotes widespread changes in cellular phenotypes through transcriptional regulation that can induce innate immunity and promote cancer. Overexpression and hyperactivity of PAD4 leads to a form of cell death called NETosis that releases PAD4 to the extracellular space. In excess, release of PAD4 is believed to be a major cause of various autoimmune diseases through the generation of anti-citrulline protein antibodies (ACPAs). Little is known about the specific protein substrates that become citrullinated and lead to autoimmunity, but there is growing evidence that PAD4 can be localized to the cell surface in response to inflammation. Here, we further characterize the cellular consequences for exogenous treatment with PAD4 showing that it induces morphological changes that increase cell migration, a hallmark of cancer. We then devised a more simplified and robust proteomics approach to identify PAD4 substrates. We identified some 1000 endogenously citrullinated peptides from 500 proteins, and 3000 citrullinated peptides from 1300 proteins upon exogenous addition of PAD4 both inside and outside of cells. This extracellular set can be further augmented by targeting PAD4 to a cancer target, HER2, using a binding protein conjugate. Finally, we studied how citrullinated cells can induce a robust humoral response in a syngeneic vaccine model to produce ACPAs. We believe these studies further our understanding of cell phenotypic consequences of extracellular PAD4 and new PAD4 substrates both inside and outside of cells that are potential neoepitopes for generation of ACPAs.

cancer biology↗

bioRxiv2025

A cytokine receptor-targeting chimera (kineTAC) toolbox for expanding extracellular targeted protein degradation.

Extracellular targeted protein degradation (eTPD) is as an important new modality for manipulating the extracellular proteome. However, most eTPD receptors are expressed broadly or are restricted to the liver. Cytokine receptor targeting chimeras (kineTACs) are genetically encoded bispecifics for eTPD that fuse a natural ligand like CXCL12 to an antibody, directing soluble or membrane proteins for lysosomal degradation using the widely expressed chemokine receptor CXCR7 (Pance K, Gramespacher JA., Byrnes, JR, Salangsang F., Serrano JAC, Cotton AD, Steri V, and Wells JA, Nat. Biotechnol. 2023, 41, 273-281). Here, we dramatically expand the kineTAC toolbox by constructing 81 new kineTACs based on an unbiased list of cytokines, chemokines and growth factors. Remarkably, 55 of these expressed at suitable levels for analysis without any optimization. Many of these kineTACs bind receptors that have unique cell-type expression profiles, allowing for eTPD in specific cells and tissues and some were more potent than the original CXCL12-based kineTAC. We further show the internalizing capability of a kineTAC can enhance the performance of antibody drug conjugates. We believe these simple, genetically encoded tools will be useful for expanding the applications for optimized or cell type-selective eTPD.

synthetic biology↗

bioRxiv2025

Low-density lipoprotein receptor-targeting chimeras for membrane protein degradation and enhanced drug delivery

Antibody-based therapeutics encompass diverse modalities for targeting tumor cells. Among these, antibody-drug conjugates (ADCs) and extracellular targeted protein degradation (eTPD) specifically depend on efficient lysosomal trafficking for activity. However, many tumor antigens exhibit poor internalization, limiting ADC effectiveness. To address this, we developed low-density lipoprotein receptor-targeting chimeras (LIPTACs), leveraging the constitutive endocytic and recycling activity of the LDLR to enhance lysosomal delivery. LIPTACs enable efficient and selective degradation of diverse extracellular membrane proteins. Additionally, by coupling LIPTACs with cytotoxic payloads to generate degrader-drug conjugates, we can achieve superior intracellular delivery and enhanced cytotoxicity compared to conventional ADCs. The dual modality addresses key challenges of inadequate internalization in conventional ADCs and cytotoxic potency for current eTPD strategies. Our findings demonstrate that LDLR-mediated trafficking can enhance eTPD and ADCs, providing a hybrid blueprint for developing next-generation antibody therapeutics with broader utility and improved efficacy in cancer treatment.

bioengineering↗

bioRxiv2025

β-Amyloid Induces Microglial Expression of GPC4 and APOE Leading to Increased Neuronal Tau Pathology and Toxicity

To elucidate the impact of A{beta} pathology on microglia in Alzheimers disease pathogenesis, we profiled the microglia surfaceome following treatment with A{beta} fibrils. Our findings reveal that A{beta}-associated human microglia upregulate Glypican 4 (GPC4), a GPI-anchored heparan sulfate proteoglycan (HSPG). In a Drosophila amyloidosis model, glial GPC4 expression exacerbates motor deficits and reduces lifespan, indicating that glial GPC4 contributes to a toxic cellular program during neurodegeneration. In cell culture, GPC4 enhances microglia phagocytosis of tau aggregates, and shed GPC4 can act in trans to facilitate tau aggregate uptake and seeding in neurons. Additionally, our data demonstrate that GPC4-mediated effects are amplified in the presence of APOE. These studies offer a mechanistic framework linking A{beta} and tau pathology through microglial HSPGs and APOE.

neuroscience↗

bioRxiv2024

Spatiotemporal photocatalytic proximity labeling proteomics reveals ligand-activated extracellular and intracellular EGFR neighborhoods

Photo-proximity labeling proteomics (PLP) methods have recently shown that the cell surface receptors can dynamically form lateral interactome networks. Here, we present a paired set of PLP workflows that simultaneously track neighborhood changes for oncogenic epidermal growth factor receptor (EGFR) with temporal resolution, both outside and inside of cells. We achieved this by augmenting the multiscale PLP workflow we call MultiMap, where three photo-probes with different labeling ranges were photo-activated by one photocatalyst, Eosin Y. By anchoring Eosin Y extracellularly and intracellularly on EGFR, we captured hundreds of proteins on both sides of the cell membrane that change in proximity to EGFR upon EGF activation. Neighbors engaged with EGFR within minutes to over an hour, reflecting dynamic interactomes during early, mid- and late-signaling including phosphorylation, internalization, degradation and transcriptional regulation. This rapid "photographic" labeling approach provides snapshots of signaling neighborhoods, revealing their dynamic nature, and potential for drug targeting.

biochemistry↗

bioRxiv2024

Evidence for reduced choroid plexus volume in the aged brain

BackgroundThe choroid plexus plays an important role in brain homeostasis, including the active secretion of cerebrospinal fluid. Its function and structure have been reported to be affected by normal ageing. However, existing measures of choroid plexus volume may be complicated by partial volume (in vivo MRI) and tissue fixation artefacts (histology). In this study, we investigate possible changes in choroid plexus volume within the lateral ventricles of aged mice utilising two structural MRI protocols explicitly designed for time-efficient, high-resolution in vivo imaging of the choroid plexus. MethodsTwo MRI sequences were utilised to examine in vivo choroid plexus volume in the lateral ventricles of young ([~]6 months) and aged ([~]24 months) mouse brains: 1) an ultra-long echo-time T2 weighted fast-spin-echo and 2) a multi-TE T2* mapping protocol. A test-retest study was performed on a subset of the data to examine the reproducibility of choroid plexus volume estimation. A two-way ANOVA test was performed to determine possible differences in choroid plexus volume in young and aged mouse groups across the two distinct MRI protocols. ResultsReproducibility tests showed a low test-retest variability of the manual segmentation pipeline for both MRI protocols. A statistically significant reduction of in vivo choroid plexus volume was found in the aged mouse brain. This finding is concordant with previous histology studies that have observed a reduction in epithelial cell height with ageing across a wide range of species. ConclusionsWe present an in vivo investigation of changes to lateral ventricle choroid plexus volume in the mouse brain utilising a manual segmentation approach based on two bespoke MRI protocols designed for time-efficient high resolution imaging of the choroid plexus. Furthermore, based on these protocols, we provide evidence for a reduction in choroid plexus volume in the aged brain. This research provides insight for studies utilising MRI measurements of choroid plexus volume as a biomarker of age-related neurologic conditions as it indicates that the ageing process itself does not result in hypertrophy of the choroid plexus, but a decrease in tissue volume.

neuroscience↗

bioRxiv2024

Hypoxia induces extensive protein and proteolytic remodeling of the cell surface in pancreatic adenocarcinoma (PDAC) cell lines

The tumor microenvironment (TME) plays a crucial role in cancer progression. Hypoxia is a hallmark of the TME and induces a cascade of molecular events that affects cellular processes involved in metabolism, metastasis, and proteolysis. In pancreatic ductal adenocarcinoma (PDAC), tumor tissues are extremely hypoxic. Here, we leveraged mass spectrometry technologies to examine hypoxia-induced alterations in the abundance and proteolytic modifications to cell surface and secreted proteins. Across four PDAC cell lines, we discovered extensive proteolytic remodeling of cell surface proteins involved in cellular adhesion and motility. Looking outward at the surrounding secreted space, we identified hypoxia-regulated secreted and proteolytically-shed proteins that are responsible for regulating the humoral immune and inflammatory response and an upregulation of proteins involved in metabolic processing and tissue development. Combining cell surface N-terminomics and secretomics to evaluate the cellular response to hypoxia enabled us to identify significantly altered candidate proteins which may serve as potential biomarkers and therapeutic targets in PDAC. Furthermore, this approach provides a blue print for studying dysregulated extracellular proteolysis in other cancers and inflammatory diseases.

cancer biology↗

bioRxiv2024

De novo design of proteins that bind naphthalenediimides, powerful photooxidants with tunable photophysical properties

De novo protein design provides a framework to test our understanding of protein function and to build proteins with cofactors and functions not found in nature. Here, we report the design of proteins designed to bind powerful photooxidants and the evaluation of the use of these proteins to generate diffusible small molecule reactive species for applications in proximity labeling. Because excited state dynamics are influenced by the dynamics and hydration of a photo-oxidants environment, it was important to not only design a binding site, but also to evaluate its dynamic properties. Thus, we used computational design in conjunction with molecular dynamics (MD) simulations to design a protein, designated NBP (NDI Binding Protein) that held a naphthalenediimide (NDI), a powerful photooxidant, in a programable molecular environment. Solution NMR confirmed the structure of the complex. We evaluated two NDI cofactors in this de novo protein, using ultra-fast pump-probe spectroscopy to evaluate light-triggered intra- and intermolecular electron transfer function. Moreover, we demonstrated the utility of this platform to activate multiple molecular probes for protein proximity labeling.

biophysics↗

bioRxiv2024

Influence of the Glymphatic System on α-Synuclein Propagation: Role of Aquaporin-4 and the Dystrophin-Associated Protein Complex

Propagation and aggregation of prion proteins, such as tau and -synuclein (Syn), are key pathological features of neurodegenerative diseases. Extracellular clearance pathways, such as the glymphatic system, may play a crucial role in the removal of these toxic proteins from the brain. Primarily active during sleep, this system relies on aquaporin-4 (AQP4) water channel expression and polarisation to astrocytic endfeet, facilitating interstitial solute clearance. Glymphatic dysfunction has recently been implicated in Parkinsons disease, however the precise mechanisms underlying the pathogenic effect of this dysfunction remain unclear. This includes how impaired glymphatic function influences Syn propagation dynamics, and the role of propagating Syn itself on glymphatic function. In this study, we used a mouse model of Syn propagation to elucidate the impact of Syn aggregation on glymphatic function, by measuring CSF-ISF exchange and assessing AQP4 and associated endfoot complex proteins in the brain over time and across different regions. Our results show that direct injection of Syn pre-formed fibrils leads to reduced expression of the AQP4 endfoot complex, but propagation of endogenous Syn induces an enhancement of glymphatic function suggesting compensatory upregulation in response to increasing endogenous Syn load. To determine the influence of glymphatic dysfunction on Syn propagation dynamics, we then employed a pharmacological approach to inhibit glymphatic function in this model. Acute glymphatic inhibition significantly reduced brain to CSF Syn clearance, and chronic treatment exacerbated Syn pathology, neurodegeneration, and motor behavioural deficits in mice. Together our findings show that Syn clearance and propagation are modulated by glymphatic function and suggest that AQP4 complex dysregulation may contribute to glymphatic impairment associated with Parkinsons diseases. Summary for the non-scientific communityThe glymphatic system clears brain waste during sleep. Lopes et al. show that -synuclein, a protein linked to Parkinsons, is cleared by this system. Using a mouse model of the disease, they suggest that aquaporin-4 water channels may impair glymphatic function, contributing to -synuclein buildup in patients brains.

neuroscience↗

bioRxiv2024

Mechanism-guided engineering of a minimal biological particle for genome editing

The widespread application of genome editing to treat or even cure disease requires the delivery of genome editors into the nucleus of target cells. Enveloped Delivery Vehicles (EDVs) are engineered virally-derived particles capable of packaging and delivering CRISPR-Cas9 ribonucleoproteins (RNPs). However, the presence of lentiviral genome encapsulation and replication components in EDVs has obscured the underlying delivery mechanism and precluded particle optimization. Here we show that Cas9 RNP nuclear delivery is independent of the native lentiviral capsid structure. Instead, EDV-mediated genome editing activity corresponds directly to the number of nuclear localization sequences on the Cas9 enzyme. EDV structural analysis using cryo-electron tomography and small molecule inhibitors guided the removal of [~]80% of viral residues, creating a minimal EDV (miniEDV) that retains full RNP delivery capability. MiniEDVs are 25% smaller yet package equivalent amounts of Cas9 RNPs relative to the original EDVs, and demonstrated increased editing in cell lines and therapeutically-relevant primary human T cells. These results show that virally-derived particles can be streamlined to create efficacious genome editing delivery vehicles that could simplify production and manufacturing. SIGNIFICANCE STATEMENTOur results highlight the importance of understanding how virally-derived particles function to eliminate unnecessary viral proteins and create more efficacious and easier-to-produce delivery vehicles for therapeutic genome editing.

bioengineering↗

bioRxiv2024

Chemoproteomics reveals immunogenic and tumor-associated cell surface substrates of ectokinase CK2α

New epitopes for immune recognition provide the basis of anticancer immunity. Due to the high concentration of extracellular adenosine triphosphate in the tumor microenvironment, we hypothesized that extracellular kinases (ectokinases) could have dysregulated activity and introduce aberrant phosphorylation sites on cell surface proteins. We engineered a cell-tethered version of the extracellular kinase CK2, demonstrated it was active on cells under tumor-relevant conditions, and profiled its substrate scope using a chemoproteomic workflow. We then demonstrated that mice developed polyreactive antisera in response to syngeneic tumor cells that had been subjected to surface hyperphosphorylation with CK2. Interestingly, these mice developed B cell and CD4+ T cell responses in response to these antigens but failed to develop a CD8+ T cell response. This work provides a workflow for probing the extracellular phosphoproteome and demonstrates that extracellular phosphoproteins are immunogenic even in a syngeneic system.

biochemistry↗

bioRxiv2024

PVRL2 Suppresses Anti-tumor Immunity Through PVRIG- and TIGIT-Independent Pathways

PVRL2 is believed to act as an immune checkpoint protein in cancer; however, most insight into PVRL2s role is inferred from studies on its known receptor PVRIG. Here, we directly study PVRL2. PVRL2 levels are high in tumor cells and tumor-derived exosomes. Deletion of PVRL2 in multiple syngeneic mouse models of cancer shows a dramatic reduction in tumor growth that is immune dependent. This effect can be even greater than seen with deletion of PD-L1. PVRL2 functions by suppressing CD8 T and NK cells in the tumor microenvironment. Unexpectedly, the effect of PVRL2 loss on tumor growth remains in the absence of PVRIG. In contrast, PVRIG loss shows no additive effect in the absence of PVRL2. TIGIT blockade combined with PVRL2 deletion results in the greatest reduction in tumor growth. This effect is not recapitulated by the combined deletion of PVRL2 with its paralog PVR, the ligand for TIGIT. These data uncover PVRL2 as a distinct inhibitor of the anti-tumor immune response with functions beyond that of its known receptor PVRIG. Importantly, the data provide a strong rationale for combinatorial targeting of PVRL2 and TIGIT for cancer immunotherapy.

immunology↗

bioRxiv2023

Multi-scale photocatalytic proximity labeling reveals cell surface neighbors on and between cells

The cell membrane proteome is the primary biohub for cell communication, yet we are only beginning to understand the dynamic protein neighborhoods that form on the cell surface and between cells. Proximity labeling proteomics (PLP) strategies using chemically reactive probes are powerful approaches to yield snapshots of protein neighborhoods but are currently limited to one single resolution based on the probe labeling radius. Here, we describe a multi-scale PLP method with tunable resolution using a commercially available histological dye, Eosin Y, which upon visible light illumination, activates three different photo-probes with labeling radii ranging from [~]100 to 3000 [A]. We applied this platform to profile neighborhoods of the oncogenic epidermal growth factor receptor (EGFR) and orthogonally validated >20 neighbors using immuno-assays and AlphaFold-Multimer prediction that generated plausible binary interaction models. We further profiled the protein neighborhoods of cell-cell synapses induced by bi-specific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR)T cells at longer length scales. This integrated multi-scale PLP platform maps local and distal protein networks on cell surfaces and between cells. We believe this information will aid in the systematic construction of the cell surface interactome and reveal new opportunities for immunotherapeutics.

biochemistry↗