Protein Science最新文献_第9页

Evaluating the potential of non-immunosuppressive cyclosporin analogs for targeting Toxoplasma gondii cyclophilin: Insights from structural studies. 评估非免疫抑制性环孢素类似物靶向弓形虫嗜环蛋白的潜力：结构研究的启示。

IF 4.5 3区生物学

Protein Science Pub Date : 2024-10-01 DOI: 10.1002/pro.5157

Filippo Favretto, Eva Jiménez-Faraco, Gianluca Catucci, Adele Di Matteo, Carlo Travaglini-Allocatelli, Sheila J Sadeghi, Paola Dominici, Juan A Hermoso, Alessandra Astegno

{"title":"Evaluating the potential of non-immunosuppressive cyclosporin analogs for targeting Toxoplasma gondii cyclophilin: Insights from structural studies.","authors":"Filippo Favretto, Eva Jiménez-Faraco, Gianluca Catucci, Adele Di Matteo, Carlo Travaglini-Allocatelli, Sheila J Sadeghi, Paola Dominici, Juan A Hermoso, Alessandra Astegno","doi":"10.1002/pro.5157","DOIUrl":"10.1002/pro.5157","url":null,"abstract":"Toxoplasmosis persists as a prevalent disease, facing challenges from parasite resistance and treatment side effects. Consequently, identifying new drugs by exploring novel protein targets is essential for effective intervention. Cyclosporin A (CsA) possesses antiparasitic activity against Toxoplasma gondii, with cyclophilins identified as possible targets. However, CsA immunosuppressive nature hinders its use as an antitoxoplasmosis agent. Here, we evaluate the potential of three CsA derivatives devoid of immunosuppressive activity, namely, NIM811, Alisporivir, and dihydrocyclosporin A to target a previously characterized cyclophilin from Toxoplasma gondii (TgCyp23). We determined the X-ray crystal structures of TgCyp23 in complex with the three analogs and elucidated their binding and inhibitory properties. The high resolution of the structures revealed the precise positioning of ligands within the TgCyp23 binding site and the details of protein-ligand interactions. A comparison with the established ternary structure involving calcineurin indicates that substitutions at position 4 in CsA derivatives prevent calcineurin binding. This finding provides a molecular explanation for why CsA analogs can target Toxoplasma cyclophilins without compromising the human immune response.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"33 10","pages":"e5157"},"PeriodicalIF":4.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142293980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A contact-based analysis of local energetic frustration dynamics identifies key residues enabling RfaH fold-switch. 基于接触的局部能量挫折动力学分析确定了实现 RfaH 折叠转换的关键残基。

IF 4.5 3区生物学

Protein Science Pub Date : 2024-10-01 DOI: 10.1002/pro.5182

Jorge González-Higueras, María Inés Freiberger, Pablo Galaz-Davison, R Gonzalo Parra, César A Ramírez-Sarmiento

{"title":"A contact-based analysis of local energetic frustration dynamics identifies key residues enabling RfaH fold-switch.","authors":"Jorge González-Higueras, María Inés Freiberger, Pablo Galaz-Davison, R Gonzalo Parra, César A Ramírez-Sarmiento","doi":"10.1002/pro.5182","DOIUrl":"https://doi.org/10.1002/pro.5182","url":null,"abstract":"Fold-switching enables metamorphic proteins to reversibly interconvert between two highly dissimilar native states to regulate their protein functions. While about 100 proteins have been identified to undergo fold-switching, unveiling the key residues behind this mechanism for each protein remains challenging. Reasoning that fold-switching in proteins is driven by dynamic changes in local energetic frustration, we combined fold-switching simulations generated using simplified structure-based models with frustration analysis to identify key residues involved in this process based on the change in the density of minimally frustrated contacts during refolding. Using this approach to analyze the fold-switch of the bacterial transcription factor RfaH, we identified 20 residues that significantly change their frustration during its fold-switch, some of which have been experimentally and computationally reported in previous works. Our approach, which we developed as an additional module for the FrustratometeR package, highlights the role of local frustration dynamics in protein fold-switching and offers a robust tool to enhance our understanding of other proteins with significant conformational shifts.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"33 10","pages":"e5182"},"PeriodicalIF":4.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11425668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142352673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An in vitro set-up to study Pdr5-mediated substrate translocation. 研究 Pdr5 介导的底物转运的体外装置。

IF 4.5 3区生物学

Protein Science Pub Date : 2024-10-01 DOI: 10.1002/pro.5181

Stefanie L Gala Marti, Manuel Wagner, Lea-Marie Nentwig, Sander H J Smits, Lutz Schmitt

{"title":"An in vitro set-up to study Pdr5-mediated substrate translocation.","authors":"Stefanie L Gala Marti, Manuel Wagner, Lea-Marie Nentwig, Sander H J Smits, Lutz Schmitt","doi":"10.1002/pro.5181","DOIUrl":"10.1002/pro.5181","url":null,"abstract":"Pdr5 is the most abundant ABC transporter in Saccharomyces cerevisiae and plays a major role in the pleiotropic drug resistance (PDR) network, which actively prevents cell entry of a large number of structurally unrelated compounds. Due to a high level of asymmetry in one of its nucleotide binding sites (NBS), Pdr5 serves as a perfect model system for asymmetric ABC transporter such as its medical relevant homologue Cdr1 from Candida albicans. In the past 30 years, this ABC transporter was intensively studied in vivo and in plasma membrane vesicles. Nevertheless, these studies were limited since it was not possible to isolate and reconstitute Pdr5 in a synthetic membrane system while maintaining its activity. Here, the functional reconstitution of Pdr5 in a native-like environment in an almost unidirectional inside-out orientation is described. We demonstrate that reconstituted Pdr5 is capable of translocating short-chain fluorescent NBD lipids from the outer to the inner leaflet of the proteoliposomes. Moreover, this transporter revealed its ability to utilize other nucleotides to accomplish transport of substrates in a reconstituted system. Besides, we were also able to estimate the NTPase activity of reconstituted Pdr5 and determine the kinetic parameters for ATP, GTP, CTP, and UTP.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"33 10","pages":"e5181"},"PeriodicalIF":4.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142293978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Multiresolution molecular dynamics simulations reveal the interplay between conformational variability and functional interactions in membrane‐bound cytochrome P450 2B4 多分辨率分子动力学模拟揭示了膜结合细胞色素 P450 2B4 的构象变化和功能相互作用之间的相互作用

IF 8 3区生物学

Protein Science Pub Date : 2024-09-18 DOI: 10.1002/pro.5165

Sungho Bosco Han, Jonathan Teuffel, Goutam Mukherjee, Rebecca C. Wade

{"title":"Multiresolution molecular dynamics simulations reveal the interplay between conformational variability and functional interactions in membrane‐bound cytochrome P450 2B4","authors":"Sungho Bosco Han, Jonathan Teuffel, Goutam Mukherjee, Rebecca C. Wade","doi":"10.1002/pro.5165","DOIUrl":"https://doi.org/10.1002/pro.5165","url":null,"abstract":"Cytochrome P450 2B4 (CYP 2B4) is one of the best‐characterized CYPs and serves as a key model system for understanding the mechanisms of microsomal class II CYPs, which metabolize most known drugs. The highly flexible nature of CYP 2B4 is apparent from crystal structures that show the active site with either a wide open or a closed heme binding cavity. Here, we investigated the conformational ensemble of the full‐length CYP 2B4 in a phospholipid bilayer, using multiresolution molecular dynamics (MD) simulations. Coarse‐grained MD simulations revealed two predominant orientations of CYP 2B4's globular domain with respect to the bilayer. Their refinement by atomistic resolution MD showed adaptation of the enzyme's interaction with the lipid bilayer, leading to open configurations that facilitate ligand access to the heme binding cavity. CAVER analysis of enzyme tunnels, AquaDuct analysis of water routes, and Random Acceleration Molecular Dynamics simulations of ligand dissociation support the conformation‐dependent passage of molecules between the active site and the protein surroundings. Furthermore, simulation of the re‐entry of the inhibitor bifonazole into the open conformation of CYP 2B4 resulted in binding at a transient hydrophobic pocket within the active site cavity that may play a role in substrate binding or allosteric regulation. Together, these results show how the open conformation of CYP 2B4 facilitates the binding of substrates from and release of products to the membrane, whereas the closed conformation prolongs the residence time of substrates or inhibitors and selectively allows the passage of smaller reactants via the solvent and water channels.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"8 1","pages":""},"PeriodicalIF":8.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular mechanisms for DNA methylation defects induced by ICF syndrome‐linked mutations in DNMT3B 与ICF综合征相关的DNMT3B突变诱发DNA甲基化缺陷的分子机制

IF 8 3区生物学

Protein Science Pub Date : 2024-09-18 DOI: 10.1002/pro.5131

Chao‐Cheng Cho, Cheng‐Yin Fei, Bo‐Chen Jiang, Wei‐Zen Yang, Hanna S. Yuan

{"title":"Molecular mechanisms for DNA methylation defects induced by ICF syndrome‐linked mutations in DNMT3B","authors":"Chao‐Cheng Cho, Cheng‐Yin Fei, Bo‐Chen Jiang, Wei‐Zen Yang, Hanna S. Yuan","doi":"10.1002/pro.5131","DOIUrl":"https://doi.org/10.1002/pro.5131","url":null,"abstract":"DNA methyltransferase 3B (DNMT3B) plays a crucial role in DNA methylation during mammalian development. Mutations in DNMT3B are associated with human genetic diseases, particularly immunodeficiency, centromere instability, facial anomalies (ICF) syndrome. Although ICF syndrome‐related missense mutations in the DNMT3B have been identified, their precise impact on protein structure and function remains inadequately explored. Here, we delve into the impact of four ICF syndrome‐linked mutations situated in the DNMT3B dimeric interface (H814R, D817G, V818M, and R823G), revealing that each of these mutations compromises DNA‐binding and methyltransferase activities to varying degrees. We further show that H814R, D817G, and V818M mutations severely disrupt the proper assembly of DNMT3B homodimer, whereas R823G does not. We also determined the first crystal structure of the methyltransferase domain of DNMT3B‐DNMT3L tetrameric complex hosting the R823G mutation showing that the R823G mutant displays diminished hydrogen bonding interactions around T775, K777, G823, and Q827 in the protein‐DNA interface, resulting in reduced DNA‐binding affinity and a shift in sequence preference of +1 to +3 flanking positions. Altogether, our study uncovers a wide array of fundamental defects triggered by DNMT3B mutations, including the disassembly of DNMT3B dimers, reduced DNA‐binding capacity, and alterations in flanking sequence preferences, leading to aberrant DNA hypomethylation and ICF syndrome.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"10 1","pages":"e5131"},"PeriodicalIF":8.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibitor binding and disruption of coupled motions in MmpL3 protein: Unraveling the mechanism of trehalose monomycolate transport MmpL3 蛋白中的抑制剂结合和耦合运动破坏：揭示三卤糖单霉素转运机制

IF 8 3区生物学

Protein Science Pub Date : 2024-09-18 DOI: 10.1002/pro.5166

Likun Zhao, Bo Liu, Henry H. Y. Tong, Xiaojun Yao, Huanxiang Liu, Qianqian Zhang

{"title":"Inhibitor binding and disruption of coupled motions in MmpL3 protein: Unraveling the mechanism of trehalose monomycolate transport","authors":"Likun Zhao, Bo Liu, Henry H. Y. Tong, Xiaojun Yao, Huanxiang Liu, Qianqian Zhang","doi":"10.1002/pro.5166","DOIUrl":"https://doi.org/10.1002/pro.5166","url":null,"abstract":"Mycobacterial membrane protein Large 3 (MmpL3) of Mycobacterium tuberculosis (Mtb) is crucial for the translocation of trehalose monomycolate (TMM) across the inner bacterial cell membrane, making it a promising target for anti‐tuberculosis (TB) drug development. While several structural, microbiological, and in vitro studies have provided significant insights, the precise mechanisms underlying TMM transport by MmpL3 and its inhibition remain incompletely understood at the atomic level. In this study, molecular dynamic (MD) simulations for the apo form and seven inhibitor‐bound forms of Mtb MmpL3 were carried out to obtain a thorough comprehension of the protein's dynamics and function. MD simulations revealed that the seven inhibitors in this work stably bind to the central channel of the transmembrane domain and primarily forming hydrogen bonds with ASP251, ASP640, or both residues. Through dynamical cross‐correlation matrix and principal component analysis analyses, several types of coupled motions between different domains were observed in the apo state, and distinct conformational states were identified using Markov state model analysis. These coupled motions and varied conformational states likely contribute to the transport of TMM. However, simulations of inhibitor‐bound MmpL3 showed an enlargement of the proton channel, potentially disrupting coupled motions. This indicates that inhibitors may impair MmpL3's transport function by directly blocking the proton channel, thereby hindering coordinated domain movements and indirectly affecting TMM translocation.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"8 1","pages":"e5166"},"PeriodicalIF":8.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mesoscale explorer: Visual exploration of large‐scale molecular models 中尺度探索者大尺度分子模型的可视化探索

IF 8 3区生物学

Protein Science Pub Date : 2024-09-18 DOI: 10.1002/pro.5177

Alexander Rose, David Sehnal, David S. Goodsell, Ludovic Autin

{"title":"Mesoscale explorer: Visual exploration of large‐scale molecular models","authors":"Alexander Rose, David Sehnal, David S. Goodsell, Ludovic Autin","doi":"10.1002/pro.5177","DOIUrl":"https://doi.org/10.1002/pro.5177","url":null,"abstract":"The advent of cryo‐electron microscopy (cryo‐EM) and cryo‐electron tomography (cryo‐ET), coupled with computational modeling, has enabled the creation of integrative 3D models of viruses, bacteria, and cellular organelles. These models, composed of thousands of macromolecules and billions of atoms, have historically posed significant challenges for manipulation and visualization without specialized molecular graphics tools and hardware. With the recent advancements in GPU rendering power and web browser capabilities, it is now feasible to render interactively large molecular scenes directly on the web. In this work, we introduce Mesoscale Explorer, a web application built using the Mol* framework, dedicated to the visualization of large‐scale molecular models ranging from viruses to cell organelles. Mesoscale Explorer provides unprecedented access and insight into the molecular fabric of life, enhancing perception, streamlining exploration, and simplifying visualization of diverse data types, showcasing the intricate details of these models with unparalleled clarity.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"51 1","pages":""},"PeriodicalIF":8.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

O‐GlcNAc modification of HSP27 alters its protein interactions and promotes refolding of proteins through the BAG3/HSP70 co‐chaperone HSP27 的 O-GlcNAc 修饰会改变其与蛋白质的相互作用，并通过 BAG3/HSP70 协同伴侣促进蛋白质的再折叠

IF 8 3区生物学

Protein Science Pub Date : 2024-09-18 DOI: 10.1002/pro.5173

Afraah Javed, Oleta T. Johnson, Aaron T. Balana, Regan F. Volk, Andreas Langen, Benjamin S. Ahn, Balyn W. Zaro, Jason E. Gestwicki, Matthew R. Pratt

{"title":"O‐GlcNAc modification of HSP27 alters its protein interactions and promotes refolding of proteins through the BAG3/HSP70 co‐chaperone","authors":"Afraah Javed, Oleta T. Johnson, Aaron T. Balana, Regan F. Volk, Andreas Langen, Benjamin S. Ahn, Balyn W. Zaro, Jason E. Gestwicki, Matthew R. Pratt","doi":"10.1002/pro.5173","DOIUrl":"https://doi.org/10.1002/pro.5173","url":null,"abstract":"Almost all types of cellular stress induce post‐translational O‐GlcNAc modifications of proteins, and this increase promotes cell survival. We previously demonstrated that O‐GlcNAc on certain small heat shock proteins (sHSPs), including HSP27, directly increases their chaperone activity as one potential protective mechanism. Here, we furthered our use of synthetic proteins to prepare biotinylated sHSPs and show that O‐GlcNAc modification of HSP27 also changes how it interacts within the sHSP system and the broader HSP network. Specifically, we show that O‐GlcNAc modified HSP27 binds more strongly to the co‐chaperone protein BAG3, which then promotes refolding of a model substrate by HSP70. We use proteomics to identify other potential HSP27 interactions that are changed by O‐GlcNAc, including one that we confirm with another sHSP, αB‐crystallin. These findings add additional evidence for O‐GlcNAc as a switch for regulating protein–protein interactions and for modifications of chaperones as one mechanism by which O‐GlcNAc protects against protein aggregation.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"54 1","pages":"e5173"},"PeriodicalIF":8.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

MeCP2 is a naturally supercharged protein with cell membrane transduction capabilities MeCP2 是一种具有细胞膜传导能力的天然超荷蛋白

IF 8 3区生物学

Protein Science Pub Date : 2024-09-14 DOI: 10.1002/pro.5170

Alexander V. Beribisky, Anna Huber, Victoria Sarne, Andreas Spittler, Nyamdelger Sukhbaatar, Teresa Seipel, Franco Laccone, Hannes Steinkellner

{"title":"MeCP2 is a naturally supercharged protein with cell membrane transduction capabilities","authors":"Alexander V. Beribisky, Anna Huber, Victoria Sarne, Andreas Spittler, Nyamdelger Sukhbaatar, Teresa Seipel, Franco Laccone, Hannes Steinkellner","doi":"10.1002/pro.5170","DOIUrl":"https://doi.org/10.1002/pro.5170","url":null,"abstract":"The intrinsically disordered protein MeCP2 is a global transcriptional regulator encoded by the MECP2 gene. Although the structured domains of MeCP2 have been the subject of multiple studies, its unstructured regions have not been that extensively characterized. In this work, we show that MeCP2 possesses properties akin to those of supercharged proteins. By utilizing its unstructured portions, MeCP2 can successfully transduce across cell membranes and localize to heterochromatic foci in the nuclei, displaying uptake levels a third lower than a MeCP2 construct fused to the cell‐penetrating peptide TAT. MeCP2 uptake can further be enhanced by the addition of compounds that promote endosomal escape following cellular trafficking by means of macropinocytosis. Using a combination of in silico prediction algorithms and live‐cell imaging experiments, we mapped the sequence in MeCP2 responsible for its cellular incorporation, which bears a striking resemblance to TAT itself. Transduced MeCP2 was shown to interact with HDAC3. These findings provide valuable insight into the properties of MeCP2 and may be beneficial for devising future protein‐based treatment strategies.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"31 1","pages":""},"PeriodicalIF":8.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

HER4 is a high‐affinity dimerization partner for all EGFR/HER/ErbB family proteins HER4 是所有表皮生长因子受体/HER/ErbB 家族蛋白的高亲和性二聚化伙伴

IF 8 3区生物学

Protein Science Pub Date : 2024-09-14 DOI: 10.1002/pro.5171

Pradeep Kumar Singh, Soyeon Kim, Adam W. Smith

{"title":"HER4 is a high‐affinity dimerization partner for all EGFR/HER/ErbB family proteins","authors":"Pradeep Kumar Singh, Soyeon Kim, Adam W. Smith","doi":"10.1002/pro.5171","DOIUrl":"https://doi.org/10.1002/pro.5171","url":null,"abstract":"Human epidermal growth factor receptors (HER)—also known as EGFR or ErbB receptors—are a subfamily of receptor tyrosine kinases (RTKs) that play crucial roles in cell growth, division, and differentiation. HER4 (ErbB4) is the least studied member of this family, partly because its expression is lower in later stages of development. Recent work has suggested that HER4 can play a role in metastasis by regulating cell migration and invasiveness; however, unlike EGFR and HER2, the precise role that HER4 plays in tumorigenesis is still unresolved. Early work on HER family proteins suggested that there are direct interactions between the four members, but to date, there has been no single study of all four receptors in the same cell line with the same biophysical method. Here, we quantitatively measure the degree of association between HER4 and the other HER family proteins in live cells with a time‐resolved fluorescence technique called pulsed interleaved excitation fluorescence cross‐correlation spectroscopy (PIE‐FCCS). PIE‐FCCS is sensitive to the oligomerization state of membrane proteins in live cells, while simultaneously measuring single‐cell protein expression levels and diffusion coefficients. Our PIE‐FCCS results demonstrate that HER4 interacts directly with all HER family members in the cell plasma membrane. The interaction between HER4 and other HER family members intensified in the presence of a HER4‐specific ligand. Our work suggests that HER4 is a preferred dimerization partner for all HER family proteins, even in the absence of ligands.","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"211 1","pages":""},"PeriodicalIF":8.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0