Proteins-Structure Function and Bioinformatics最新文献

{"title":"The Crystal Structure of Human IgD-Fc Reveals Unexpected Differences With Other Antibody Isotypes.","authors":"Anna M Davies, Tam T T Bui, Raúl Pacheco-Gómez, Susan K Vester, Andrew J Beavil, Hannah J Gould, Brian J Sutton, James M McDonnell","doi":"10.1002/prot.26771","DOIUrl":"10.1002/prot.26771","url":null,"abstract":"<p><p>Of the five human antibody isotypes, the function of IgD is the least well-understood, although various studies point to a role for IgD in mucosal immunity. IgD is also the least well structurally characterized isotype. Until recently, when crystal structures were reported for the IgD Fab, the only structural information available was a model for intact IgD based on solution scattering data. We now report the crystal structure of human IgD-Fc solved at 3.0 Å resolution. Although similar in overall architecture to other human isotypes, IgD-Fc displays markedly different orientations of the Cδ3 domains in the Cδ3 domain dimer and the lowest interface area of all the human isotypes. The nature of the residues that form the dimer interface also differs from those conserved in the other isotypes. By contrast, the interface between the Cδ2 and Cδ3 domains in each chain is the largest among the human isotypes. This interface is characterized by two binding pockets, not seen in other isotypes, and points to a potential role for the Cδ2/Cδ3 interface in stabilizing the IgD-Fc homodimer. We investigated the thermal stability of IgD-Fc, alone and in the context of an intact IgD antibody, and found that IgD-Fc unfolds in a single transition. Human IgD-Fc clearly has unique structural features not seen in the other human isotypes, and comparison with other mammalian IgD sequences suggests that these unique features might be widely conserved.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"786-800"},"PeriodicalIF":3.2,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11878202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142711704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PCANN Program for Structure-Based Prediction of Protein-Protein Binding Affinity: Comparison With Other Neural-Network Predictors.","authors":"Olga O Lebedenko, Mikhail S Polovinkin, Anastasiia A Kazovskaia, Nikolai R Skrynnikov","doi":"10.1002/prot.26821","DOIUrl":"https://doi.org/10.1002/prot.26821","url":null,"abstract":"<p><p>In this communication, we introduce a new structure-based affinity predictor for protein-protein complexes. This predictor, dubbed PCANN (Protein Complex Affinity by Neural Network), uses the ESM-2 language model to encode the information about protein binding interfaces and graph attention network (GAT) to parlay this information into <math> <semantics> <mrow><msub><mi>K</mi> <mi>d</mi></msub> </mrow> <annotation>$$ {K}_{mathrm{d}} $$</annotation></semantics> </math> predictions. In the tests employing two previously unused literature-extracted datasets, PCANN performed better than the best of the publicly available predictors, BindPPI, with mean absolute error (MAE) of 1.3 versus 1.4 kcal/mol. Further progress in the development of <math> <semantics> <mrow><msub><mi>K</mi> <mi>d</mi></msub> </mrow> <annotation>$$ {K}_{mathrm{d}} $$</annotation></semantics> </math> predictors using deep learning models is faced with two problems: (i) the amount of experimental data available to train and test new predictors is limited and (ii) the available <math> <semantics> <mrow><msub><mi>K</mi> <mi>d</mi></msub> </mrow> <annotation>$$ {K}_{mathrm{d}} $$</annotation></semantics> </math> data are often not very accurate and lack internal consistency with respect to measurement conditions. These issues can be potentially addressed through an AI-leveraged literature search followed by careful human curation and by introducing additional parameters to account for variations in experimental conditions.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143671758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Overview of Property, Design, and Functionality of Linkers for Fusion Protein Construction.","authors":"Hadis Chatrdooz, Javad Sargolzaei","doi":"10.1002/prot.26812","DOIUrl":"https://doi.org/10.1002/prot.26812","url":null,"abstract":"<p><p>Linkers are naturally occurring short amino acid sequences that are used to separate domains within a protein. The advent of recombinant DNA technology has made it possible to combine two interacting partners by introducing artificial linkers that often, allow for the production of stable and functional proteins. Glycine-rich linkers are useful for transient interactions, especially where the interaction is weak, by covalently linking proteins and forming a stable protein-protein complex. These linkers have also been used to generate covalently stable dimers and to connect two independent domains that create a ligand binding site or recognition sequence. Various structures of covalently linked protein complexes have been described using nuclear magnetic resonance methods, cryo-electron microscopy techniques, and X-ray crystallography; in addition, several structures where linkers have been used to generate stable protein-protein complexes, improve protein solubility, and obtain protein dimers are investigated, and also the design and engineering of the linker in fusion proteins is discussed. Therefore, one of the main factors for linker design and optimization is their flexibility, which can directly contribute to the physical distance between the domains of a fusion protein and describe the tendency of a linker to maintain a stable conformation during expression. We summarize the research on design and bioinformatics can be used to predict the spatial structure of the fusion protein. To perform simulations of spatial structures and drug molecule design, future research will concentrate on various correlation models.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143659812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative Protein Assembly With LZerD and Deep Learning in CAPRI 47-55.","authors":"Charles Christoffer, Yuki Kagaya, Jacob Verburgt, Genki Terashi, Woong-Hee Shin, Anika Jain, Daipayan Sarkar, Tunde Aderinwale, Sai Raghavendra Maddhuri Venkata Subramaniya, Xiao Wang, Zicong Zhang, Yuanyuan Zhang, Daisuke Kihara","doi":"10.1002/prot.26818","DOIUrl":"https://doi.org/10.1002/prot.26818","url":null,"abstract":"<p><p>We report the performance of the protein complex prediction approaches of our group and their results in CAPRI Rounds 47-55, excluding the joint CASP Rounds 50 and 54, as well as the special COVID-19 Round 51. Our approaches integrated classical pipelines developed in our group as well as more recently developed deep learning pipelines. In the cases of human group prediction, we surveyed the literature to find information to integrate into the modeling, such as assayed interface residues. In addition to any literature information, generated complex models were selected by a rank aggregation of statistical scoring functions, by generative model confidence, or by expert inspection. In these CAPRI rounds, our human group successfully modeled eight interfaces and achieved the top quality level among the submissions for all of them, including two where no other group did. We note that components of our modeling pipelines have become increasingly unified within deep learning approaches. Finally, we discuss several case studies that illustrate successful and unsuccessful modeling using our approaches.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143652274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Actin-Binding Prolyl-Isomerase Par17 Sustains Its Substrate Selectivity by Interdomain Allostery.","authors":"Anna Sternberg, Jennifer Lynne Borger, Mathilda Thies, Anja Matena, Mike Blueggel, Bianca E Kamba, Christine Beuck, Farnusch Kaschani, Markus Kaiser, Peter Bayer","doi":"10.1002/prot.26807","DOIUrl":"https://doi.org/10.1002/prot.26807","url":null,"abstract":"<p><p>The human peptidyl-prolyl-cis/trans isomerases (PPIases), Parvulin 14 and Parvulin 17, accelerate the cis/trans isomerization of Xaa-Pro moieties within protein sequences. By modulating the respective binding interfaces of their target proteins, they play a crucial role in determining the fate of their substrates within the cell. Although both enzymes share the same amino acid sequence, they have different cellular functions. This difference is due to a 25 residue N-terminal extension present in Par17 but absent in Par14. Using activity assays, NMR spectroscopy, and mass spectrometry, we demonstrate that the N-terminal extension of Par17 determines substrate selectivity by an intramolecular allosteric mechanism and exhibits a target-binding motif that interacts with actin.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143607313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insights Into the Conformational Dynamics of the Cytoplasmic Domain of Metal-Sensing Sensor Histidine Kinase ZraS.","authors":"Nilima Mahapatra, Pranjal Mahanta, Shubhant Pandey, Rudresh Acharya","doi":"10.1002/prot.26819","DOIUrl":"https://doi.org/10.1002/prot.26819","url":null,"abstract":"<p><p>ZraS is a metal sensor integral to ZraPSR, a two-component signaling system found in enterobacters. It belongs to a family of bifunctional sensor histidine kinases (SHKs) and is speculated to sense zinc-induced stress on the bacterial envelope. Information on the structure-function relationship of sensor kinases is elusive due to the lack of full-length structures, intrinsically dynamic behavior, and difficulty trapping them in active state conformations. While the kinase domains (KDs) of a few SHKs are well characterized, they exhibit significant functional diversity attributed to their modular multi-domain arrangement in the cytoplasmic region, combined with other signal transducing elements such as simple helices, HAMP, and PAS domains. We report the crystal structure of the entire cytoplasmic region of Escherichia coli ZraS (EcZraS-CD) resolved at a resolution of 2.49 Å, comprising a unique helical linker and the KD. In the asymmetric unit, four molecules of ZraS assemble as homodimers trapped as two ligand-bound occluded conformers. Our analysis using these conformers shows that modulation of the dimer bundle through segmental helical bending, sliding, and rotation leads to the reorganization of the dimerization interface during kinase activation. Further, our analysis reveals the significance of aromatic amino acid interactions and loop residues at the dimer base in regulating the directionality of rotation during autophosphorylation. We also performed an in vitro coupled assay to determine ATPase activity. Overall, our findings provide structure-based mechanistic insights into the process of autophosphorylation in trans-acting SHKs.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating Local Sequence-Structural Attributes of Amyloidogenic Light Chain Variable Domains.","authors":"Puneet Rawat, R Prabakaran, Divya Sharma, Vasanth Mandala, Victor Greiff, Sandeep Kumar, M Michael Gromiha","doi":"10.1002/prot.26815","DOIUrl":"https://doi.org/10.1002/prot.26815","url":null,"abstract":"<p><p>Light chain amyloidosis is a medical condition characterized by the aggregation of misfolded antibody light chains into insoluble amyloid fibrils in the target organs, causing organ dysfunction, organ failure, and death. Despite extensive research to understand the factors contributing to amyloidogenesis, accurately predicting whether a given protein will form amyloids under specific conditions remains a formidable challenge. In this study, we have conducted a comprehensive analysis to understand the amyloidogenic tendencies within a dataset containing 1828 (348 amyloidogenic and 1480 non-amyloidogenic) antibody light chain variable region (V_L) sequences obtained from the AL-Base database. Physicochemical and structural features often associated with protein aggregation, such as net charge, isoelectric point (pI), and solvent-exposed hydrophobic regions did not reveal a consistent association with the aggregation capability of the antibody light chains. However, the solvent-exposed aggregation-prone regions (APRs) occur with higher frequencies among the amyloidogenic light chains when compared with the non-amyloidogenic ones, with the difference ranging from 2% to 15% at various relative solvent-accessible surface area (rASA) cutoffs. We have, for the first time, identified structural gatekeeping residues around the APRs and assessed their impact on the amyloidogenicity of the antibody light chains. The non-amyloidogenic light chains contain these structural gatekeeper residues vicinal to their APRs more often than the amyloidogenic ones. We observed that the rASA cutoff of 35% is optimal for identifying the surface-exposed APRs, and a 4 Å distance cutoff from the APR motif(s) is optimal for identifying the structural gatekeeper residues. Moreover, lambda light chains were found to contain solvent-exposed APRs more often and surrounded by fewer gatekeepers, rendering them more susceptible to aggregation. The insights gained from this report have significant implications for understanding the molecular origins of light-chain amyloidosis in humans and the design of aggregation-resistant therapeutic antibodies.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding the Role of RING-Between-RING E3 Ligase of the Human Malaria Parasite.","authors":"Varsha Kumari, Seema Vidyarthi, Aradhya Tripathi, Nirupa Chaurasia, Niharika Rai, Richa Shukla, Shagufa Nisrat Noorie, Girdhar Bhati, Simmi Anjum, Mohammad Anas, Shakil Ahmed, Niti Kumar","doi":"10.1002/prot.26813","DOIUrl":"https://doi.org/10.1002/prot.26813","url":null,"abstract":"<p><p>E3 ligases constitute an important component of proteostasis machinery, which plays a critical role in the survival of malaria parasites through post-translational modifications of their protein substrates. In contrast to humans, parasite E3 ligases have not been extensively studied. Here, we characterize a unique Plasmodium E3 ligase that has both RING and HECT-like features with zinc-coordinating domains. Plasmodium encodes a single RING-between-RING (RBR) E3 ligase that has evolutionarily diverged from human and other intracellular parasites. This RBR-E3 ligase is expressed throughout the erythrocytic phase of the P. falciparum lifecycle. Immunoprecipitation experiments showed that Pf RBR-E3 ligase catalyzes K6, K11, K48, and K63 mediated polyubiquitination, hinting towards its probable biological roles (DNA repair, proteasomal degradation, mitochondrial quality control). We observed that Pf RBR-E3 ligase interacts with UBCH5 and UBC13 family of E2-conjugating enzymes. Through mutational analysis in Pf RBR-E3 ligase, we identified residues in RING1 and RING2 domains that are critical for ubiquitination activity and its protein stability. Pf RBR-E3 ligase exhibits differences in immunofluorescence profile upon exposure of the parasite to different genotoxic (MMS) and proteotoxic (MG132, FCCP and artemisinin derivative) stress. Our study opens up avenues for exploring the client substrates of Pf RBR-E3 ligase and using this knowledge to design substrate-specific protein degradation-based alternative intervention strategies for malaria.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544641","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural Implications of HIV-1 Protease Subtype C Bound to Darunavir: A Molecular Dynamics Study.","authors":"Sankaran Venkatachalam, Sowmya Ramaswamy Krishnan, Ramesh Pandian, Yasien Sayed, M Michael Gromiha","doi":"10.1002/prot.26817","DOIUrl":"https://doi.org/10.1002/prot.26817","url":null,"abstract":"<p><p>In recent years, Human Immunodeficiency Virus (HIV) remains a significant global health challenge, with millions affected worldwide, particularly in Africa and sub-Saharan regions. Despite advances in antiretroviral therapies, the genetic variability of HIV, including different subtypes and drug-resistant strains, poses persistent obstacles in the development of universally effective treatments. This study focuses on the dynamics of HIV protease, a key enzyme in viral replication and maturation, particularly targeting subtype C and its double insertion (HL) variant L38HL, in the context of interaction with Darunavir (DRV), a second-generation nonpeptidic protease inhibitor approved by the FDA in 2006. Through molecular dynamics simulations, structural analyses, dynamic cross-correlation analyses, and binding energy calculations, we investigated differences in the binding of DRV to WT and L38HL HIV-1 protease. The findings highlight that the double insertion at the hinge induces variation in Φ and Ψ angles, leading to increased residue fluctuations, solvent-accessible surface area (SASA), and radius of gyration (R_g). This alters the overall structural compactness and the hydrophobic core crucial for drug binding. Subtle structural changes result in the loss of hydrogen bond interactions, reducing the binding energy of L38HL HIV-1 protease subtype C bound to DRV, leading to drug resistance.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Towards a Greener AlphaFold2 Protocol for Antibody-Antigen Modeling: Insights From CAPRI Round 55.","authors":"Büşra Savaş, İrem Yılmazbilek, Atakan Özsan, Ezgi Karaca","doi":"10.1002/prot.26820","DOIUrl":"https://doi.org/10.1002/prot.26820","url":null,"abstract":"<p><p>In the 55th round of CAPRI, we used enhanced AlphaFold2 (AF2) sampling and data-driven docking. Our AF2 protocol relies on Wallner's massive sampling approach, which combines different AF2 versions and sampling parameters to produce thousands of models per target. For T231 (an antibody-peptide complex) and T232 (PP2A:TIPRL complex), we employed a 50-fold reduced MinnieFold sampling and a custom ranking approach, leading to a top-ranking medium prediction in both cases. For T233 and T234 (two antibody bound MHC I complexes), we followed data-driven docking, which did not lead to an acceptable model. Our post-CAPRI55 analysis showed that if we had used our MinnieFold approach on T233 and T234, we could have submitted a medium-quality model for T233 as well. In the scoring challenge, we utilized the scoring function of FoldX, which was effective in selecting acceptable models for T231 and medium-quality models for T232. Our success, especially in predicting and ranking a medium-quality model for T231 and potentially for T233, underscores the feasibility of green and accurate enhanced AF2 sampling in antibody complex prediction.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}