StructurePub Date : 2024-10-08DOI: 10.1016/j.str.2024.09.015
Sewwandi S. Rathnayake, Satchal K. Erramilli, Anthony A. Kossiakoff, Alex J. Vecchio
{"title":"Cryo-EM structures of Clostridium perfringens enterotoxin bound to its human receptor, claudin-4","authors":"Sewwandi S. Rathnayake, Satchal K. Erramilli, Anthony A. Kossiakoff, Alex J. Vecchio","doi":"10.1016/j.str.2024.09.015","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.015","url":null,"abstract":"<em>Clostridium perfringens</em> enterotoxin (CpE) causes prevalent and deadly gastrointestinal disorders. CpE binds to receptors called claudins on the apical surfaces of small intestinal epithelium. Claudins normally regulate paracellular transport but are hijacked from doing so by CpE and are instead led to form claudin/CpE complexes. Claudin/CpE complexes are the building blocks of oligomeric β-barrel pores that penetrate the plasma membrane and induce gut cytotoxicity. Here, we present the structures of CpE in complex with its native claudin receptor in humans, claudin-4, using cryogenic electron microscopy. The structures reveal the architecture of the claudin/CpE complex, the residues used in binding, the orientation of CpE relative to the membrane, and CpE-induced changes to claudin-4. Further, structures and modeling allude to the biophysical procession from claudin/CpE complexes to cytotoxic β-barrel pores during pathogenesis. In full, this work proposes a model of claudin/CpE assembly and provides strategies to obstruct its formation to treat CpE diseases.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"6 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
StructurePub Date : 2024-10-08DOI: 10.1016/j.str.2024.09.013
Vladyslava Sokolova, Jacob Miratsky, Vladimir Svetlov, Michael Brenowitz, John Vant, Tyler S. Lewis, Kelly Dryden, Gahyun Lee, Shayan Sarkar, Evgeny Nudler, Abhishek Singharoy, Dongyan Tan
{"title":"Structural mechanism of HP1⍺-dependent transcriptional repression and chromatin compaction","authors":"Vladyslava Sokolova, Jacob Miratsky, Vladimir Svetlov, Michael Brenowitz, John Vant, Tyler S. Lewis, Kelly Dryden, Gahyun Lee, Shayan Sarkar, Evgeny Nudler, Abhishek Singharoy, Dongyan Tan","doi":"10.1016/j.str.2024.09.013","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.013","url":null,"abstract":"Heterochromatin protein 1 (HP1) plays a central role in establishing and maintaining constitutive heterochromatin. However, the mechanisms underlying HP1-nucleosome interactions and their contributions to heterochromatin functions remain elusive. Here, we present the cryoelectron microscopy (cryo-EM) structure of an HP1α dimer bound to an H2A.Z-nucleosome, revealing two distinct HP1α-nucleosome interfaces. The primary HP1α binding site is located at the N terminus of histone H3, specifically at the trimethylated lysine 9 (K9me3) region, while a secondary binding site is situated near histone H2B, close to nucleosome superhelical location 4 (SHL4). Our biochemical data further demonstrates that HP1α binding influences the dynamics of DNA on the nucleosome. It promotes DNA unwrapping near the nucleosome entry and exit sites while concurrently restricting DNA accessibility in the vicinity of SHL4. Our study offers a model for HP1α-mediated heterochromatin maintenance and gene silencing. It also sheds light on the H3K9me-independent role of HP1 in responding to DNA damage.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"225 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
StructurePub Date : 2024-10-08DOI: 10.1016/j.str.2024.09.014
Nikita A. Egorkin, Eva E. Dominnik, Roman I. Raevskii, Daria D. Kuklina, Larisa A. Varfolomeeva, Vladimir O. Popov, Konstantin M. Boyko, Nikolai N. Sluchanko
{"title":"Structural basis of selective beta-carotene binding by a soluble protein","authors":"Nikita A. Egorkin, Eva E. Dominnik, Roman I. Raevskii, Daria D. Kuklina, Larisa A. Varfolomeeva, Vladimir O. Popov, Konstantin M. Boyko, Nikolai N. Sluchanko","doi":"10.1016/j.str.2024.09.014","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.014","url":null,"abstract":"β-carotene (BCR) is the most abundant carotenoid, a colorant, antioxidant, and provitamin A. The extreme hydrophobicity of this hydrocarbon requires special mechanisms for distribution in aqueous media, including water-soluble carotenoproteins. However, all known carotenoproteins prefer oxygenated carotenoids and bind BCR inefficiently. Here, we present the crystal structure of the BCR-binding protein (BBP) from gregarious male locusts, which is responsible for their vivid yellow body coloration, in complex with its natural ligand, BCR. BBP forms an antiparallel tubular homodimer with α/β-wrap folded monomers, each forming a hydrophobic 47 Å long, coaxial tunnel that opens outward and is occupied by one s-cis<sup>C6-C7</sup>, all-trans BCR molecule. In the BCR absence, BBP accepts a range of xanthophylls, with reduced efficiency depending on the position and number of oxygen atoms, but rejects lycopene. The structure captures a pigment complex with a Takeout 1 protein and inspires potential applications of BBP as a BCR solubilizer.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"64 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Structural biology of the human papillomavirus","authors":"Feng Han, Xin-ying Guo, Ming-xia Jiang, Ning-shao Xia, Ying Gu, Shao-wei Li","doi":"10.1016/j.str.2024.09.011","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.011","url":null,"abstract":"Human papillomavirus (HPV), known for its oncogenic properties, is the primary cause of cervical cancer and significantly contributes to mortality rates. It also plays a considerable role in the globally rising incidences of head and neck cancers. These cancers pose a substantial health burden worldwide. Current limitations in diagnostic and treatment strategies, along with inadequate coverage of preventive vaccines in low- and middle-income countries, hinder the progress toward the World Health Organization (WHO) HPV prevention and control targets set for 2030. In response to these challenges, extensive research in structural virology has explored the properties of HPV proteins, yielding crucial insights into the mechanisms of HPV infection that are important for the development of prevention and therapeutic strategies. This review highlights recent advances in understanding the structures of HPV proteins and discusses achievements and future opportunities for HPV vaccine development.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"192 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
StructurePub Date : 2024-10-04DOI: 10.1016/j.str.2024.09.010
Mu Gao, Jeffrey Skolnick
{"title":"Predicting protein interactions of the kinase Lck critical to T cell modulation","authors":"Mu Gao, Jeffrey Skolnick","doi":"10.1016/j.str.2024.09.010","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.010","url":null,"abstract":"Protein-protein interactions (PPIs) play pivotal roles in directing T cell fate. One key player is the non-receptor tyrosine protein kinase Lck that helps to transduce T cell activation signals. Lck is mediated by other proteins via interactions that are inadequately understood. Here, we use the deep learning method AF2Complex to predict PPIs involving Lck, by screening it against ∼1,000 proteins implicated in immune responses, followed by extensive structural modeling for selected interactions. Remarkably, we describe how Lck may be specifically targeted by a palmitoyltransferase using a phosphotyrosine motif. We uncover “hotspot” interactions between Lck and the tyrosine phosphatase CD45, leading to a significant conformational shift of Lck for activation. Lastly, we present intriguing interactions between the phosphotyrosine-binding domain of Lck and the cytoplasmic tail of the immune checkpoint LAG3 and propose a molecular mechanism for its inhibitory role. Together, this multifaceted study provides valuable insights into T cell regulation and signaling.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"112 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Mechanism of phospho-Ubls’ specificity and conformational changes that regulate Parkin activity","authors":"Dipti Ranjan Lenka, Shradha Chaurasiya, Loknath Ratnakar, Atul Kumar","doi":"10.1016/j.str.2024.09.012","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.012","url":null,"abstract":"PINK1 and Parkin mutations lead to the early onset of Parkinson’s disease. PINK1-mediated phosphorylation of ubiquitin (Ub), ubiquitin-like protein (NEDD8), and ubiquitin-like (Ubl) domain of Parkin activate autoinhibited Parkin E3 ligase. The mechanism of various phospho-Ubls’ specificity and conformational changes leading to Parkin activation remain elusive. Herein, we show that compared to Ub, NEDD8 is a more robust binder and activator of Parkin. Structures and biophysical/biochemical data reveal specific recognition and underlying mechanisms of pUb/pNEDD8 and pUbl domain binding to the RING1 and RING0 domains, respectively. Also, pUb/pNEDD8 binding in the RING1 pocket promotes allosteric conformational changes in Parkin’s catalytic domain (RING2), leading to Parkin activation. Furthermore, Parkinson’s disease mutation K211N in the RING0 domain was believed to perturb Parkin activation due to loss of pUb binding. However, our data reveal allosteric conformational changes due to N211 that lock RING2 with RING0 to inhibit Parkin activity without disrupting pNEDD8/pUb binding.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"47 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
StructurePub Date : 2024-10-03DOI: 10.1016/j.str.2024.09.008
Shuvankar Dey, Purba Pahari, Srija Mukherjee, James B. Munro, Dibyendu Kumar Das
{"title":"Conformational dynamics of SARS-CoV-2 Omicron spike trimers during fusion activation at single molecule resolution","authors":"Shuvankar Dey, Purba Pahari, Srija Mukherjee, James B. Munro, Dibyendu Kumar Das","doi":"10.1016/j.str.2024.09.008","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.008","url":null,"abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron entry involves spike (S) glycoprotein-mediated fusion of viral and late endosomal membranes. Here, using single-molecule Förster resonance energy transfer (sm-FRET) imaging and biochemical measurements, we directly visualized conformational changes of individual spike trimers on the surface of SARS-CoV-2 Omicron pseudovirions during fusion activation. We observed that the S2 domain of the Omicron spike is a dynamic fusion machine. S2 reversibly interchanges between the pre-fusion conformation and two previously undescribed intermediate conformations. Acidic pH shifts the conformational equilibrium of S2 toward an intermediate conformation and promotes the membrane hemi-fusion reaction. Moreover, we captured conformational reversibility in the S2 domain, which suggests that spike can protect itself from pre-triggering. Furthermore, we determined that Ca<sup>2+</sup> directly promotes the S2 conformational change from an intermediate conformation to post-fusion conformation. In the presence of a target membrane, low pH and Ca<sup>2+</sup> stimulate the irreversible transition to S2 post-fusion state and promote membrane fusion.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"222 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
StructurePub Date : 2024-10-03Epub Date: 2024-08-15DOI: 10.1016/j.str.2024.07.015
Jana Škerlová, Jiří Brynda, Jan Šobotník, Marek Zákopčaník, Petr Novák, Thomas Bourguignon, David Sillam-Dussès, Pavlína Řezáčová
{"title":"Crystal structure of blue laccase BP76, a unique termite suicidal defense weapon.","authors":"Jana Škerlová, Jiří Brynda, Jan Šobotník, Marek Zákopčaník, Petr Novák, Thomas Bourguignon, David Sillam-Dussès, Pavlína Řezáčová","doi":"10.1016/j.str.2024.07.015","DOIUrl":"10.1016/j.str.2024.07.015","url":null,"abstract":"<p><p>Aging workers of the termite Neocapritermes taracua can defend their colony by sacrificing themselves by body rupture, mixing the externally stored blue laccase BP76 with hydroquinones to produce a sticky liquid rich in toxic benzoquinones. Here, we describe the crystal structure of BP76 isolated from N. taracua in its native form. The structure reveals several stabilization strategies, including compact folding, glycosylation, and flexible loops with disulfide bridges and tight dimer interface. The remarkable stability of BP76 maintains its catalytic activity in solid state during the lifespan of N. taracua workers, providing old workers with an efficient defensive weapon to protect their colony.</p>","PeriodicalId":22168,"journal":{"name":"Structure","volume":" ","pages":"1581-1585.e5"},"PeriodicalIF":4.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141996546","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
StructurePub Date : 2024-10-03Epub Date: 2024-08-26DOI: 10.1016/j.str.2024.07.023
Daniel M Pinkas, Joshua C Bufton, Alice E Hunt, Charlotte E Manning, William Richardson, Alex N Bullock
{"title":"A BTB extension and ion-binding domain contribute to the pentameric structure and TFAP2A binding of KCTD1.","authors":"Daniel M Pinkas, Joshua C Bufton, Alice E Hunt, Charlotte E Manning, William Richardson, Alex N Bullock","doi":"10.1016/j.str.2024.07.023","DOIUrl":"10.1016/j.str.2024.07.023","url":null,"abstract":"<p><p>KCTD family proteins typically assemble into cullin-RING E3 ligases. KCTD1 is an atypical member that functions instead as a transcriptional repressor. Mutations in KCTD1 cause developmental abnormalities and kidney fibrosis in scalp-ear-nipple syndrome. Here, we present unexpected mechanistic insights from the structure of human KCTD1. Disease-causing mutation P20S maps to an unrecognized extension of the BTB domain that contributes to both its pentameric structure and TFAP2A binding. The C-terminal domain (CTD) shares its fold and pentameric assembly with the GTP cyclohydrolase I feedback regulatory protein (GFRP) despite lacking discernible sequence similarity. Most surprisingly, the KCTD1 CTD establishes a central channel occupied by alternating sodium and iodide ions that restrict TFAP2A dissociation. The elucidation of the structure redefines the KCTD1 BTB domain fold and identifies an unexpected ion-binding site for future study of KCTD1's function in the ectoderm, neural crest, and kidney.</p>","PeriodicalId":22168,"journal":{"name":"Structure","volume":" ","pages":"1586-1593.e4"},"PeriodicalIF":4.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142081553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
StructurePub Date : 2024-10-03DOI: 10.1016/j.str.2024.09.007
Radha Charan Dash, Gianluca A. Arianna, Seema M. Patel, Alessandro A. Rizzo, Noah J. Harrahill, Dmitry M. Korzhnev, M. Kyle Hadden
{"title":"Probing hot spots of protein-protein interactions mediated by the safety-belt region of REV7","authors":"Radha Charan Dash, Gianluca A. Arianna, Seema M. Patel, Alessandro A. Rizzo, Noah J. Harrahill, Dmitry M. Korzhnev, M. Kyle Hadden","doi":"10.1016/j.str.2024.09.007","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.007","url":null,"abstract":"REV7 is a HORMA (<u>H</u>op1, <u>R</u>ev7, <u>M</u>ad2) family adaptor protein best known as an accessory subunit of the translesion synthesis (TLS) DNA polymerase ζ (Polζ). In this role, REV7 binds REV3, the catalytic subunit of Polζ, by locking REV7-binding motifs (RBMs) in REV3 underneath the REV7 safety-belt loop. The same mechanism is used by REV7 to interact with RBMs from other proteins in DNA damage response (DDR) and mitosis. Because of the importance of REV7 for TLS and other DDR pathways, targeting REV7:RBM protein-protein interactions (PPIs) with small molecules has emerged as a strategy to enhance cancer response to genotoxic chemotherapy. To identify druggable pockets at the REV7:RBM interface, we performed computational analyses of REV7 complexed with several RBM partners. The contributions of different interface regions to REV7:RBM stabilization were corroborated experimentally. These studies provide insights into key intermolecular interactions and establish targetable regions of REV7 for the design of REV7:RBM PPI inhibitors.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"57 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}