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Mining the UniProtKB/Swiss-Prot database for antimicrobial peptides. 挖掘UniProtKB/Swiss-Prot抗菌肽数据库。
IF 4.5 3区 生物学
Protein Science Pub Date : 2025-04-01 DOI: 10.1002/pro.70083
Chenkai Li, Darcy Sutherland, Ali Salehi, Amelia Richter, Diana Lin, Sambina Islam Aninta, Hossein Ebrahimikondori, Anat Yanai, Lauren Coombe, René L Warren, Monica Kotkoff, Linda M N Hoang, Caren C Helbing, Inanc Birol
{"title":"Mining the UniProtKB/Swiss-Prot database for antimicrobial peptides.","authors":"Chenkai Li, Darcy Sutherland, Ali Salehi, Amelia Richter, Diana Lin, Sambina Islam Aninta, Hossein Ebrahimikondori, Anat Yanai, Lauren Coombe, René L Warren, Monica Kotkoff, Linda M N Hoang, Caren C Helbing, Inanc Birol","doi":"10.1002/pro.70083","DOIUrl":"10.1002/pro.70083","url":null,"abstract":"<p><p>The ever-growing global health threat of antibiotic resistance is compelling researchers to explore alternatives to conventional antibiotics. Antimicrobial peptides (AMPs) are emerging as a promising solution to fill this need. Naturally occurring AMPs are produced by all forms of life as part of the innate immune system. High-throughput bioinformatics tools have enabled fast and large-scale discovery of AMPs from genomic, transcriptomic, and proteomic resources of selected organisms. Public protein sequence databases, comprising over 200 million records and growing, serve as comprehensive compendia of sequences from a broad range of source organisms. Yet, large-scale in silico probing of those databases for novel AMP discovery using modern deep learning techniques has rarely been reported. In the present study, we propose an AMP mining workflow to predict novel AMPs from the UniProtKB/Swiss-Prot database using the AMP prediction tool, AMPlify, as its discovery engine. Using this workflow, we identified 8008 novel putative AMPs from all eukaryotic sequences in the database. Focusing on the practical use of AMPs as suitable antimicrobial agents with applications in the poultry industry, we prioritized 40 of those AMPs based on their similarities to known chicken AMPs in predicted structures. In our tests, 13 out of the 38 successfully synthesized peptides showed antimicrobial activity against Escherichia coli and/or Staphylococcus aureus. AMPlify and the companion scripts supporting the AMP mining workflow presented herein are publicly available at https://github.com/bcgsc/AMPlify.</p>","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 4","pages":"e70083"},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11917140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657176","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
Sizes, conformational fluctuations, and SAXS profiles for intrinsically disordered proteins. 大小,构象波动,和本质上无序的蛋白质SAXS谱。
IF 4.5 3区 生物学
Protein Science Pub Date : 2025-04-01 DOI: 10.1002/pro.70067
Mauro L Mugnai, Debayan Chakraborty, Hung T Nguyen, Farkhad Maksudov, Abhinaw Kumar, Wade Zeno, Jeanne C Stachowiak, John E Straub, D Thirumalai
{"title":"Sizes, conformational fluctuations, and SAXS profiles for intrinsically disordered proteins.","authors":"Mauro L Mugnai, Debayan Chakraborty, Hung T Nguyen, Farkhad Maksudov, Abhinaw Kumar, Wade Zeno, Jeanne C Stachowiak, John E Straub, D Thirumalai","doi":"10.1002/pro.70067","DOIUrl":"10.1002/pro.70067","url":null,"abstract":"&lt;p&gt;&lt;p&gt;The preponderance of intrinsically disordered proteins (IDPs) in the eukaryotic proteome, and their ability to interact with each other, and with folded proteins, RNA, and DNA for functional purposes, have made it important to quantitatively characterize their biophysical properties. Toward this end, we developed the transferable self-organized polymer (SOP-IDP) model to calculate the properties of several IDPs. The values of the radius of gyration ( &lt;math&gt; &lt;semantics&gt; &lt;mrow&gt;&lt;msub&gt;&lt;mi&gt;R&lt;/mi&gt; &lt;mi&gt;g&lt;/mi&gt;&lt;/msub&gt; &lt;/mrow&gt; &lt;annotation&gt;$$ {R}_g $$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; ) obtained from SOP-IDP simulations are in excellent agreement (correlation coefficient of 0.96) with those estimated from SAXS experiments. For AP180 and Epsin, the predicted values of the hydrodynamic radii ( &lt;math&gt; &lt;semantics&gt; &lt;mrow&gt;&lt;msub&gt;&lt;mi&gt;R&lt;/mi&gt; &lt;mi&gt;h&lt;/mi&gt;&lt;/msub&gt; &lt;mi&gt;s&lt;/mi&gt;&lt;/mrow&gt; &lt;annotation&gt;$$ {R}_hmathrm{s} $$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; ) are in nearly quantitative agreement with those from fluorescence correlation spectroscopy (FCS) experiments. Strikingly, the calculated SAXS profiles for 36 IDPs are also nearly superimposable on the experimental profiles. The dependence of &lt;math&gt; &lt;semantics&gt; &lt;mrow&gt;&lt;msub&gt;&lt;mi&gt;R&lt;/mi&gt; &lt;mi&gt;g&lt;/mi&gt;&lt;/msub&gt; &lt;/mrow&gt; &lt;annotation&gt;$$ {R}_g $$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; and the mean end-to-end distance ( &lt;math&gt; &lt;semantics&gt; &lt;mrow&gt;&lt;msub&gt;&lt;mi&gt;R&lt;/mi&gt; &lt;mi&gt;ee&lt;/mi&gt;&lt;/msub&gt; &lt;/mrow&gt; &lt;annotation&gt;$$ {R}_{ee} $$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; ) on chain length, &lt;math&gt; &lt;semantics&gt;&lt;mrow&gt;&lt;mi&gt;N&lt;/mi&gt;&lt;/mrow&gt; &lt;annotation&gt;$$ N $$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; , follows Flory's scaling law, &lt;math&gt; &lt;semantics&gt; &lt;mrow&gt;&lt;msub&gt;&lt;mi&gt;R&lt;/mi&gt; &lt;mi&gt;α&lt;/mi&gt;&lt;/msub&gt; &lt;mo&gt;≈&lt;/mo&gt; &lt;msub&gt;&lt;mi&gt;a&lt;/mi&gt; &lt;mi&gt;α&lt;/mi&gt;&lt;/msub&gt; &lt;msup&gt;&lt;mi&gt;N&lt;/mi&gt; &lt;mn&gt;0.588&lt;/mn&gt;&lt;/msup&gt; &lt;/mrow&gt; &lt;annotation&gt;$$ {R}_{alpha}approx {a}_{alpha }{N}^{0.588} $$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; ( &lt;math&gt; &lt;semantics&gt;&lt;mrow&gt;&lt;mi&gt;α&lt;/mi&gt; &lt;mo&gt;=&lt;/mo&gt; &lt;mi&gt;g&lt;/mi&gt; &lt;mo&gt;,&lt;/mo&gt;&lt;/mrow&gt; &lt;annotation&gt;$$ alpha =g, $$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; and &lt;math&gt; &lt;semantics&gt;&lt;mrow&gt;&lt;mi&gt;e&lt;/mi&gt;&lt;/mrow&gt; &lt;annotation&gt;$$ e $$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; ), suggesting that globally IDPs behave as synthetic polymers in a good solvent. This finding depends on the solvent quality, which can be altered by changing variables such as pH and salt concentration. The values of &lt;math&gt; &lt;semantics&gt; &lt;mrow&gt;&lt;msub&gt;&lt;mi&gt;a&lt;/mi&gt; &lt;mi&gt;g&lt;/mi&gt;&lt;/msub&gt; &lt;/mrow&gt; &lt;annotation&gt;$$ {a}_g $$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; and &lt;math&gt; &lt;semantics&gt; &lt;mrow&gt;&lt;msub&gt;&lt;mi&gt;a&lt;/mi&gt; &lt;mi&gt;e&lt;/mi&gt;&lt;/msub&gt; &lt;/mrow&gt; &lt;annotation&gt;$$ {a}_e $$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; are 0.20 and 0.48 nm, respectively. Surprisingly, finite size corrections to scaling, expected on theoretical grounds, are negligible for &lt;math&gt; &lt;semantics&gt; &lt;mrow&gt;&lt;msub&gt;&lt;mi&gt;R&lt;/mi&gt; &lt;mi&gt;g&lt;/mi&gt;&lt;/msub&gt; &lt;/mrow&gt; &lt;annotation&gt;$$ {R}_g $$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; and &lt;math&gt; &lt;semantics&gt; &lt;mrow&gt;&lt;msub&gt;&lt;mi&gt;R&lt;/mi&gt; &lt;mi&gt;ee&lt;/mi&gt;&lt;/msub&gt; &lt;/mrow&gt; &lt;annotation&gt;$$ {R}_{ee} $$&lt;/annotation&gt;&lt;/semantics&gt; &lt;/math&gt; . In contrast, only by account","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 4","pages":"e70067"},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143650314","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 conserved motif in Henipavirus P/V/W proteins drives the fibrillation of the W protein from Hendra virus. 亨尼帕病毒P/V/W蛋白中的一个保守基序驱动亨德拉病毒W蛋白的纤颤。
IF 4.5 3区 生物学
Protein Science Pub Date : 2025-04-01 DOI: 10.1002/pro.70085
Frank Gondelaud, Christophe Bignon, Denis Ptchelkine, Frédéric Carrière, Sonia Longhi
{"title":"A conserved motif in Henipavirus P/V/W proteins drives the fibrillation of the W protein from Hendra virus.","authors":"Frank Gondelaud, Christophe Bignon, Denis Ptchelkine, Frédéric Carrière, Sonia Longhi","doi":"10.1002/pro.70085","DOIUrl":"10.1002/pro.70085","url":null,"abstract":"<p><p>The Hendra (HeV) and Nipah (NiV) viruses are high-priority, biosafety level-4 pathogens that cause fatal neurological and respiratory disease. Their P gene encodes not only the P protein, an essential polymerase cofactor, but also the virulence factors V and W. We previously showed that the W protein of HeV (W<sup>HeV</sup>) forms amyloid-like fibrils and that one of its subdomains, PNT3, fibrillates in isolation. However, the fibrillation kinetics is much faster in the case of the full-length W<sup>HeV</sup> compared to PNT3, suggesting that another W<sup>HeV</sup> region contributes to the fibrillation process. In this work, we identified the region spanning residues 2-110 (PNT1) as the crucial region implicated in W<sup>HeV</sup> fibrillation. Through site-directed mutagenesis, combined with thioflavin T binding experiments and negative-staining transmission electron microscopy, we showed that a predicted cryptic amyloidogenic region (CAR) within PNT1 is the main driver of fibrillation and deciphered the underlying molecular mechanism. Using FTIR, we showed that PNT1 fibrils are enriched in cross β-sheets. Sequence alignment revealed conservation of the CAR across the Henipavirus genus and enabled the identification of a hitherto never reported pro-amyloidogenic motif. The ability to form fibrils was experimentally shown to be a common property shared by Henipavirus PNT1 proteins. Overall, this study sheds light on the molecular mechanisms underlying W<sup>HeV</sup> fibrillation and calls for future studies aimed at exploring the relevance of the newly identified pro-amyloidogenic motif as a valuable target for antiviral approaches.</p>","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 4","pages":"e70085"},"PeriodicalIF":4.5,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11917119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143658388","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
Non-canonical ORFs-derived protein products in mitochondria: A multifaceted exploration of their functions in health and disease. 线粒体中非规范orfs衍生的蛋白质产物:其在健康和疾病中的功能的多方面探索。
IF 4.5 3区 生物学
Protein Science Pub Date : 2025-03-01 DOI: 10.1002/pro.70053
Ikram Ajala, Benoît Vanderperre
{"title":"Non-canonical ORFs-derived protein products in mitochondria: A multifaceted exploration of their functions in health and disease.","authors":"Ikram Ajala, Benoît Vanderperre","doi":"10.1002/pro.70053","DOIUrl":"10.1002/pro.70053","url":null,"abstract":"<p><p>Traditionally, eukaryotic mRNAs were perceived as inherently monocistronic. However, recent insights from ribosome profiling (Ribo-seq) and proteomics studies challenge this paradigm. These investigations reveal that, beyond the currently annotated reference proteins (RefProts), there exist additional proteins known as alternative proteins (AltProts) and small open reading frames derived microproteins encoded in regions of mRNAs previously considered untranslated or in non-coding transcripts. This experimental evidence broadens the spectrum of functional proteins within cells, tissues, and organs, potentially offering crucial insights into biological processes. Notably, a significant proportion of these newly identified AltProts and microproteins demonstrates localization in mitochondria, contributing to the functions of mitochondrial complexes. This review delves into the overlooked realm of the alternative proteome within mitochondria, exploring the role of nuclear or mitochondrial-genome-encoded AltProts and microproteins in physiological and pathological cellular processes.</p>","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 3","pages":"e70053"},"PeriodicalIF":4.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450033","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
Exploring P450 superfamily diversity with P450Atlas - Online tool for automated subfamily assignment. 使用P450Atlas探索P450超家族多样性-用于自动亚家族分配的在线工具。
IF 4.5 3区 生物学
Protein Science Pub Date : 2025-03-01 DOI: 10.1002/pro.70057
Dominik Gront, Khajamohiddin Syed, David R Nelson
{"title":"Exploring P450 superfamily diversity with P450Atlas - Online tool for automated subfamily assignment.","authors":"Dominik Gront, Khajamohiddin Syed, David R Nelson","doi":"10.1002/pro.70057","DOIUrl":"10.1002/pro.70057","url":null,"abstract":"<p><p>Cytochrome P450 monooxygenases (CYPs/P450s) are heme-containing enzymes known to biology for more than six decades. Their stereo- and regio-specific enzymatic activities on various compounds led to exploring their potential in almost all areas of life. The P450 superfamily, encompassing nearly 10,000 known families, boasts a staggering diversity represented by numerous families, highlighting its immense scale within the realm of enzymes. In this contribution, we describe the P450Atlas website: the ultimate source of information about all named P450 families and subfamilies. The website's main functionality is the automated assignment of a query sequence to one of the known subfamilies. The new subfamily assignment algorithm relies on Hidden Markov Models (HMM) and has been extensively tested and compared to an approach based on the BLAST program. Extensive validation shows that the HMM approach is more sensitive than the latter one, offering almost perfect automated P450 sequence assignment to subfamilies. A user can also browse and search through the online list of families across the Tree of Life. We believe that the P450Atlas website (https://p450atlas.org) will become a comprehensive and unified source of information on cytochrome 450 nomenclature.</p>","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 3","pages":"e70057"},"PeriodicalIF":4.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837033/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449924","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
ShiftScan: A tool for rapid analysis of high-throughput differential scanning fluorimetry data and compound prioritization. ShiftScan:用于快速分析高通量差分扫描荧光数据和化合物优先级的工具。
IF 4.5 3区 生物学
Protein Science Pub Date : 2025-03-01 DOI: 10.1002/pro.70055
Samantha C Waterworth, Shilpa R Shenoy, Nirmala D Sharma, Chris Wolcott, Duncan E Donohue, Barry R O'Keefe, John A Beutler
{"title":"ShiftScan: A tool for rapid analysis of high-throughput differential scanning fluorimetry data and compound prioritization.","authors":"Samantha C Waterworth, Shilpa R Shenoy, Nirmala D Sharma, Chris Wolcott, Duncan E Donohue, Barry R O'Keefe, John A Beutler","doi":"10.1002/pro.70055","DOIUrl":"10.1002/pro.70055","url":null,"abstract":"<p><p>Differential scanning fluorimetry (DSF) can be an effective high-throughput screening assay in drug discovery for detecting protein-compound interactions that stabilize or destabilize macromolecules. Due to the magnitude and quality of the data produced by this biophysical assay, analyzing and prioritizing compounds from large-scale DSF data sets has proven challenging to the research community. Here, we present ShiftScan-a powerful, stand-alone tool designed for the rapid analysis of DSF data and compound prioritization based on thermal transition patterns. ShiftScan accurately and quickly predicts melting temperatures (Tm values) from both canonical and non-canonical transition patterns, efficiently filtering out spurious data to minimize false positives. We report on the use of this tool for data analysis of screens involving both pure compound and natural product fraction libraries and provide the software to the screening community to aid in the discovery of molecularly-targeted compounds. Instructions for installation and usage of ShiftScan can be found at our GitHub repository: https://github.com/samche42/ShiftScan.</p>","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 3","pages":"e70055"},"PeriodicalIF":4.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11848206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483816","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
Exploring the proton transport mechanism of the mitochondrial ADP/ATP carrier: FA-cycling hypothesis and beyond. 探索线粒体ADP/ATP载体的质子转运机制:fa循环假说及其后续。
IF 4.5 3区 生物学
Protein Science Pub Date : 2025-03-01 DOI: 10.1002/pro.70047
Elena E Pohl, Mario Vazdar, Jürgen Kreiter
{"title":"Exploring the proton transport mechanism of the mitochondrial ADP/ATP carrier: FA-cycling hypothesis and beyond.","authors":"Elena E Pohl, Mario Vazdar, Jürgen Kreiter","doi":"10.1002/pro.70047","DOIUrl":"10.1002/pro.70047","url":null,"abstract":"<p><p>The mitochondrial ADP/ATP carrier (AAC, ANT), a member of the SLC25 family of solute carriers, plays a critical role in transporting purine nucleotides (ATP and ADP) as well as protons across the inner mitochondrial membrane. However, the precise mechanism and physiological significance of proton transport by ADP/ATP carrier remain unclear. Notably, the presence of uncouplers-such as long-chain fatty acids (FA) or artificial compounds like dinitrophenol (DNP)-is essential for this process. We explore two potential mechanisms that describe ADP/ATP carrier as either (i) a proton carrier that functions in the presence of FA or DNP, or (ii) an anion transporter (FA<sup>-</sup> or DNP). In the latter case, the proton is translocated by the neutral form of FA, which carries it from the matrix to the intermembrane space (FA-cycling hypothesis). Our recent results support this hypothesis. We describe a four-step mechanism for the \"sliding\" of the FA anion from the matrix to the mitochondrial intermembrane space and discuss a possible generalization of this mechanism to other SLC25 carriers.</p>","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 3","pages":"e70047"},"PeriodicalIF":4.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837047/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449926","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
Engineering IGF2 for Lysosome-targeting chimeras development to target drug-resistant membrane proteins in tumor therapy. 工程IGF2用于溶酶体靶向嵌合体的开发,以靶向耐药膜蛋白治疗肿瘤。
IF 4.5 3区 生物学
Protein Science Pub Date : 2025-03-01 DOI: 10.1002/pro.70051
Yanchao Pan, Qing Xiang, Kai Deng, Muhammad I Anwar, Leiming Wang, Yuan Wang, Qiulian Liang, Lirou Shen, Jing Yang, Zhongyu Hou, Weijun Shen
{"title":"Engineering IGF2 for Lysosome-targeting chimeras development to target drug-resistant membrane proteins in tumor therapy.","authors":"Yanchao Pan, Qing Xiang, Kai Deng, Muhammad I Anwar, Leiming Wang, Yuan Wang, Qiulian Liang, Lirou Shen, Jing Yang, Zhongyu Hou, Weijun Shen","doi":"10.1002/pro.70051","DOIUrl":"10.1002/pro.70051","url":null,"abstract":"<p><p>Lysosome-targeting chimeras (LYTACs) represent a promising approach for the targeted degradation of membrane proteins. Currently, two primary methods for LYTAC development involve chemically modified antibodies and wild-type insulin-like growth factor 2 (IGF2) fusion proteins (iLYTACs). However, LYTACs necessitate intricate chemical modification processes, while wild-type IGF2 in iLYTAC technology binds to IGF1R, potentially triggering carcinogenesis. To tackle this challenge, we introduce specific IGF2R-binding lysosomal targeting chimeras (sLYTACs), a novel technology utilizing engineered IGF2 mutant fusion antibodies for the degradation of endogenous membrane proteins. Diverging from iLYTACs, sLYTACs exhibit selective binding to IGF2R with increased affinity, significantly bolstering the anti-proliferative impact on drug-resistant tumor cells both in vitro and in vivo. By effectively degrading third-generation tyrosine kinase inhibitor-resistant EGFR mutants, masking binding epitope HER2, and concurrently targeting compensatory receptors interacting with these proteins, sLYTACs show great promise in drug development to overcome bypass signaling and combat drug resistance in tumors.</p>","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 3","pages":"e70051"},"PeriodicalIF":4.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143449919","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
Refinement and curation of homologous groups facilitated by structure prediction. 结构预测促进了同源基团的精化和整理。
IF 4.5 3区 生物学
Protein Science Pub Date : 2025-03-01 DOI: 10.1002/pro.70074
Richard Dustin Schaeffer, Jimin Pei, Jing Zhang, Qian Cong, Nick V Grishin
{"title":"Refinement and curation of homologous groups facilitated by structure prediction.","authors":"Richard Dustin Schaeffer, Jimin Pei, Jing Zhang, Qian Cong, Nick V Grishin","doi":"10.1002/pro.70074","DOIUrl":"10.1002/pro.70074","url":null,"abstract":"<p><p>Domain classification of protein predictions released in the AlphaFold Database (AFDB) has been a recent focus of the Evolutionary Classification of protein Domains (ECOD). Although a primary focus of our recent work has been the partition and assignment of domains from these predictions, we here show how these diverse predictions can be used to examine the reference domain set more closely. Using results from DPAM, our AlphaFold-specific domain parsing algorithm, we examine hierarchical groupings that share significant levels of homologous links, both between groups that were not previously assessed to be definitively homologous and between groups that were not previously observed to share significant homologous links. Combined with manual analysis, these large datasets of structural and sequence similarities allow us to merge homologous groups in multiple cases which we detail within. These domains tend to be families of domains from families that are either small, previously had few experimental representatives, or had unknown function. The exception to this is the chromodomains, a large homologous group which were increased from \"possibly homologous\" to \"definitely homologous\" to increase the consistency of ECOD based their strong homologous links to the SH3 domains.</p>","PeriodicalId":20761,"journal":{"name":"Protein Science","volume":"34 3","pages":"e70074"},"PeriodicalIF":4.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11836899/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450195","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
From duplication to fusion: Expanding Dayhoff's model of protein evolution. 从复制到融合:扩展戴霍夫的蛋白质进化模型。
IF 4.5 3区 生物学
Protein Science Pub Date : 2025-03-01 DOI: 10.1002/pro.70054
Yusran Abdillah Muthahari, Lilian Magnus, Paola Laurino
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