Biophysical chemistry最新文献

{"title":"Key arginine residues in R2D2 dsRBD1 and dsRBD2 lead the siRNA recognition in Drosophila melanogaster RNAi pathway","authors":"Ramdas Aute ,&nbsp;Nilam Waghela ,&nbsp;Mandar V. Deshmukh","doi":"10.1016/j.bpc.2024.107247","DOIUrl":"https://doi.org/10.1016/j.bpc.2024.107247","url":null,"abstract":"<div><p>In <em>Drosophila melanogaster</em>, Dcr-2:R2D2 heterodimer binds to the 21 nucleotide siRNA duplex to form the R2D2/Dcr-2 Initiator (RDI) complex, which is critical for the initiation of siRNA-induced silencing complex (RISC) assembly. During RDI complex formation, R2D2, a protein that contains three dsRNA binding domains (dsRBD), senses two aspects of the siRNA: thermodynamically more stable end (asymmetry sensing) and the 5′-phosphate (5<em>'</em><em>-</em>P) recognition. Despite several detailed studies to date, the molecular determinants arising from R2D2 for performing these two tasks remain elusive. In this study, we have performed structural, biophysical, and biochemical characterization of R2D2 dsRBDs. We found that the solution NMR-derived structure of R2D2 dsRBD1 yielded a canonical α1-β1-β2-β3-α2 fold, wherein two arginine salt bridges provide additional stability to the R2D2 dsRBD1. Furthermore, we show that R2D2 dsRBD1 interacts with thermodynamically asymmetric siRNA duplex independent of its 5′-phosphorylation state, whereas R2D2 dsRBD2 prefers to interact with 5<em>'</em>-P siRNA duplex. The mutation of key arginine residues, R53 and R101, in concatenated dsRBDs of R2D2 results in a significant loss of siRNA duplex recognition. Our study deciphers the active roles of R2D2 dsRBDs by showing that dsRBD1 initiates siRNA recognition, whereas dsRBD2 senses 5′-phosphate as an authentic mark on functional siRNA.</p></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"310 ","pages":"Article 107247"},"PeriodicalIF":3.8,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140643587","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}

{"title":"Thermodynamics of oligomerization and Helix-to-sheet structural transition of amyloid β-protein on anionic phospholipid vesicles","authors":"Keisuke Ikeda,&nbsp;Yuuki Sugiura,&nbsp;Hiroyuki Nakao,&nbsp;Minoru Nakano","doi":"10.1016/j.bpc.2024.107248","DOIUrl":"https://doi.org/10.1016/j.bpc.2024.107248","url":null,"abstract":"<div><p>Understanding oligomerization and aggregation of the amyloid-β protein is important to elucidate the pathological mechanisms of Alzheimer's disease, and lipid membranes play critical roles in this process. In addition to studies reported by other groups, our group has also reported that the negatively-charged lipid bilayers with a high positive curvature induced α-helix-to-β-sheet conformational transitions of amyloid-β-(1–40) upon increase in protein density on the membrane surface and promoted amyloid fibril formation of the protein. Herein, we investigated detailed mechanisms of the conformational transition and oligomer formation of the amyloid-β protein on the membrane surface. Changes in the fractions of the three protein conformers (free monomer, membrane-bound α-helix-rich conformation, and β-sheet-rich conformation) were determined from the fluorescent spectral changes of the tryptophan probe in the protein. The helix-to-sheet structural transition on the surface was described by a thermodynamic model of octamer formation driven by entropic forces including hydrophobic interactions. These findings provide useful information for understanding the self-assembly of amyloidogenic proteins on lipid membrane surfaces.</p></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"310 ","pages":"Article 107248"},"PeriodicalIF":3.8,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140638239","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}

{"title":"Structural packing of the non-amyloid component core domain in α-synuclein plays a role in the stability of the fibrils","authors":"Karina Abramov-Harpaz ,&nbsp;Sapir Lan-Mark ,&nbsp;Yifat Miller","doi":"10.1016/j.bpc.2024.107239","DOIUrl":"https://doi.org/10.1016/j.bpc.2024.107239","url":null,"abstract":"<div><p>Parkinson's disease (PD) is one of many neurodegenerative diseases. The protein associated with PD is α-synuclein (AS). Aggregation of AS protein into oligomers, protofilaments, and finally to fibrils yields to the development of PD. The aggregation process of AS leads to the formation of polymorphic AS fibrils. Herein, we compared four polymorphic full-length AS₁_–₁₄₀ fibrils, using extensive computational tools. The main conclusion of this study emphasizes the role of the structurally packed non-amyloid component (NAC) core domain in AS fibrils. Polymorphic AS fibrils that presented a packed NAC core domain, exhibited more β-sheets and fewer fluctuations in the NAC domain. Hence, these AS fibrils are more stable and populated than the AS fibrils, by which the NAC domains are more exposed, more fluctuate and less packed in the fibrillary structure. Therefore, this study emphasizes the importance of the NAC domain packing in the morphology of AS fibrils. The results obtained in this study will initiate future studies to develop compounds to prevent and inhibit AS aggregation.</p></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"310 ","pages":"Article 107239"},"PeriodicalIF":3.8,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140643588","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}

{"title":"Insights into the mechanism of peptide fibril growth on gold surface","authors":"Soumya Mondal,&nbsp;Tarak Karmakar","doi":"10.1016/j.bpc.2024.107237","DOIUrl":"https://doi.org/10.1016/j.bpc.2024.107237","url":null,"abstract":"<div><p>Understanding the formation of <em>β</em>-fibrils over the gold surface is of paramount interest in nano-bio-medicinal Chemistry. The intricate mechanism of self-assembly of neurofibrillogenic peptides and their growth over the gold surface remains elusive, as experiments are limited in unveiling the microscopic dynamic details, in particular, at the early stage of the peptide aggregation. In this work, we carried out equilibrium molecular dynamics and enhanced sampling simulations to elucidate the underlying mechanism of the growth of an amyloid-forming sequence of tau fragments over the gold surface. Our results disclose that the collective intermolecular interactions between the peptide chains and peptides with the gold surface facilitate the peptide adsorption, followed by integration, finally leading to the fibril formation.</p></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"310 ","pages":"Article 107237"},"PeriodicalIF":3.8,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140605984","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}

{"title":"Nano-bio convergence unveiled: Systematic review on quantum dots-protein interaction, their implications, and applications","authors":"Jagriti Gupta,&nbsp;Pradeep Kumar Vaid,&nbsp;Eepsita Priyadarshini,&nbsp;Paulraj Rajamani","doi":"10.1016/j.bpc.2024.107238","DOIUrl":"10.1016/j.bpc.2024.107238","url":null,"abstract":"<div><p>Quantum dots (QDs) are semiconductor nanocrystals (2–10 nm) with unique optical and electronic properties due to quantum confinement effects. They offer high photostability, narrow emission spectra, broad absorption spectrum, and high quantum yields, making them versatile in various applications. Due to their highly reactive surfaces, QDs can conjugate with biomolecules while being used, produced, or unintentionally released into the environment. This systematic review delves into intricate relationship between QDs and proteins, examining their interactions that influence their physicochemical properties, enzymatic activity, ligand binding affinity, and stability. The research utilized electronic databases like PubMed, WOS, and Proquest, along with manual reviews from 2013 to 2023 using relevant keywords, to identify suitable literature. After screening titles and abstracts, only articles meeting inclusion criteria were selected for full text readings. This systematic review of 395 articles identifies 125 articles meeting the inclusion criteria, categorized into five overarching themes, encompassing various mechanisms of QDs and proteins interactions, including adsorption to covalent binding, contingent on physicochemical properties of QDs. Through a meticulous analysis of existing literature, it unravels intricate nature of interaction, significant influence on nanomaterials and biological entities, and potential for synergistic applications harnessing both specific and nonspecific interactions across various fields.</p></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"310 ","pages":"Article 107238"},"PeriodicalIF":3.8,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140755992","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}

{"title":"Experimental and computational investigation of the effect of Hsc70 structural variants on inhibiting amylin aggregation","authors":"Ali Chaari ,&nbsp;Nabanita Saikia ,&nbsp;Pradipta Paul ,&nbsp;Mohammad Yousef ,&nbsp;Feng Ding ,&nbsp;Moncef Ladjimi","doi":"10.1016/j.bpc.2024.107235","DOIUrl":"https://doi.org/10.1016/j.bpc.2024.107235","url":null,"abstract":"<div><p>The misfolding and aggregation of human islet amyloid polypeptide (hIAPP), also known as amylin, have been implicated in the pathogenesis of type 2 diabetes (T2D). Heat shock proteins, specifically, heat shock cognate 70 (Hsc70), are molecular chaperones that protect against hIAPP misfolding and inhibits its aggregation. Nevertheless, there is an incomplete understanding of the mechanistic interactions between Hsc70 domains and hIAPP, thus limiting their potential therapeutic role in diabetes. This study investigates the inhibitory capacities of different Hsc70 variants, aiming to identify the structural determinants that strike a balance between efficacy and cytotoxicity. Our experimental findings demonstrate that the ATPase activity of Hsc70 is not a pivotal factor for inhibiting hIAPP misfolding. We underscore the significance of the C-terminal substrate-binding domain of Hsc70 in inhibiting hIAPP aggregation, emphasizing that the removal of the lid subdomain diminishes the inhibitory effect of Hsc70. Additionally, we employed atomistic discrete molecular dynamics simulations to gain deeper insights into the interaction between Hsc70 variants and hIAPP. Integrating both experimental and computational findings, we propose a mechanism by which Hsc70's interaction with hIAPP monomers disrupts protein-protein connections, primarily by shielding the β-sheet edges of the Hsc70-β-sandwich. The distinctive conformational dynamics of the alpha helices of Hsc70 potentially enhance hIAPP binding by obstructing the exposed edges of the β-sandwich, particularly at the β5-β8 region along the alpha helix interface. This, in turn, inhibits fibril growth, and similar results were observed following hIAPP dimerization. Overall, this study elucidates the structural intricacies of Hsc70 crucial for impeding hIAPP aggregation, improving our understanding of the potential anti-aggregative properties of molecular chaperones in diabetes treatment.</p></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"309 ","pages":"Article 107235"},"PeriodicalIF":3.8,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0301462224000644/pdfft?md5=9c201f2ba0e25f0b8371ffcb99e4ae4d&pid=1-s2.0-S0301462224000644-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140543193","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}

{"title":"Inhibition of insulin fibrillation by carboxyphenylboronic acid-modified chitosan oligosaccharide based on electrostatic interactions and hydrophobic interactions","authors":"Xiangyuan Zhao ,&nbsp;Chunyan Yang ,&nbsp;Wei Liu ,&nbsp;Ke Lu ,&nbsp;Hao Yin","doi":"10.1016/j.bpc.2024.107236","DOIUrl":"https://doi.org/10.1016/j.bpc.2024.107236","url":null,"abstract":"<div><p>A novel inhibitor, carboxyphenylboronic acid-modified chitosan oligosaccharide (COS-CPBA), was developed by coupling carboxyphenylboronic acid (CPBA) with chitosan oligosaccharide (COS) to inhibit insulin fibrillation. Extensive biophysical assays indicated that COS-CPBA could decelerate insulin aggregation, hinder the conformational transition from α-helix to β-sheet structure, change the morphology of insulin aggregates and alter fibrillation pathway. A mechanism for the inhibition of insulin fibrillation by COS-CPBA was proposed. It considers that insulin molecules bind to COS-CPBA via hydrophobic interactions, while the positively charged groups in COS-CPBA exert electrostatic repulsion on the bound insulin molecules. These two opposite forces cause the insulin molecules to display extended conformations and hinder the conformational transition of insulin from α-helix to β-sheet structure necessary for fibrillation, thus decelerating aggregation and altering the fibrillation pathway of insulin. The studies provide novel ideas for the development of more effective inhibitors of amyloid fibrillation.</p></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"310 ","pages":"Article 107236"},"PeriodicalIF":3.8,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140552343","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}

{"title":"Mechanistic insights into G-protein activation via phosphorylation mediated non-canonical pathway","authors":"Kunal Shewani ,&nbsp;Midhun K. Madhu ,&nbsp;Rajesh K. Murarka","doi":"10.1016/j.bpc.2024.107234","DOIUrl":"https://doi.org/10.1016/j.bpc.2024.107234","url":null,"abstract":"<div><p>Activation of heterotrimeric G-proteins (<span><math><mi>G</mi><mi>αβγ</mi></math></span>) downstream to receptor tyrosine kinases (RTKs) is a well-established crosstalk between the signaling pathways mediated by G-protein coupled receptors (GPCRs) and RTKs. While GPCR serves as a guanine exchange factor (GEF) in the canonical activation of <span><math><mi>G</mi><mi>α</mi></math></span> that facilitates the exchange of GDP for GTP, the mechanism through which RTK phosphorylations induce <span><math><mi>G</mi><mi>α</mi></math></span> activation remains unclear. Recent experimental studies revealed that the epidermal growth factor receptor (EGFR), a well-known RTK, phosphorylates the helical domain tyrosine residues Y154 and Y155 and accelerates the GDP release from the <span><math><mi>G</mi><mi>α</mi><mi>i</mi><mn>3</mn></math></span>, a subtype of <span><math><mi>G</mi><mi>α</mi></math></span>-protein. Using well-tempered metadynamics and extensive unbiased molecular dynamics simulations, we captured the GDP release event and identified the intermediates between bound and unbound states through Markov state models. In addition to weakened salt bridges at the domain interface, phosphorylations induced the unfolding of helix <span><math><mi>α</mi><mi>F</mi></math></span>, which contributed to increased flexibility near the hinge region, facilitating a greater distance between domains in the phosphorylated <span><math><mi>G</mi><mi>α</mi><mi>i</mi><mn>3</mn></math></span>. Although the larger domain separation in the phosphorylated system provided an unobstructed path for the nucleotide, the accelerated release of GDP was attributed to increased fluctuations in several conserved regions like P-loop, switch 1, and switch 2. Overall, this study provides atomistic insights into the activation of G-proteins induced by RTK phosphorylations and identifies the specific structural motifs involved in the process. The knowledge gained from the study could establish a foundation for targeting non-canonical signaling pathways and developing therapeutic strategies against the ailments associated with dysregulated G-protein signaling.</p></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"309 ","pages":"Article 107234"},"PeriodicalIF":3.8,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140542635","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}

{"title":"Structural analysis of ATP bound to the F1-ATPase β-subunit monomer by solid-state NMR- insight into the hydrolysis mechanism in F1","authors":"Yasuto Todokoro ,&nbsp;Yoshiyuki Miyasaka ,&nbsp;Hiromasa Yagi ,&nbsp;Masatsune Kainosho ,&nbsp;Toshimichi Fujiwara ,&nbsp;Hideo Akutsu","doi":"10.1016/j.bpc.2024.107232","DOIUrl":"https://doi.org/10.1016/j.bpc.2024.107232","url":null,"abstract":"<div><p>ATP-hydrolysis-associated conformational change of the <em>β</em>-subunit during the rotation of F₁-ATPase (F₁) has been discussed using cryo-electron microscopy (cryo-EM). Since it is worthwhile to further investigate the conformation of ATP at the catalytic subunit through an alternative approach, the structure of ATP bound to the F₁<em>β</em>-subunit monomer (<em>β</em>) was analyzed by solid-state NMR. The adenosine conformation of ATP-<em>β</em> was similar to that of ATP analog in F₁ crystal structures. ³¹P chemical shift analysis showed that the P^α and P^β conformations of ATP-<em>β</em> are gauche-trans and trans-trans, respectively. The triphosphate chain is more extended in ATP-<em>β</em> than in ATP analog in F₁ crystals. This appears to be in the state just before ATP hydrolysis. Furthermore, the ATP-<em>β</em> conformation is known to be more closed than the closed form in F₁ crystal structures. In view of the cryo-EM results, ATP-<em>β</em> would be a model of the most closed <em>β</em>-subunit with ATP ready for hydrolysis in the hydrolysis stroke of the F₁ rotation.</p></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"309 ","pages":"Article 107232"},"PeriodicalIF":3.8,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140535191","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}

{"title":"New insights into the interaction of emodin with lipid membranes","authors":"Antonio R. da Cunha ,&nbsp;Evandro L. Duarte ,&nbsp;Gabriel S. Vignoli Muniz ,&nbsp;Kaline Coutinho ,&nbsp;M. Teresa Lamy","doi":"10.1016/j.bpc.2024.107233","DOIUrl":"https://doi.org/10.1016/j.bpc.2024.107233","url":null,"abstract":"<div><p>Emodin is a natural anthraquinone derivative found in nature, widely known as an herbal medicine. Here, the partition, location, and interaction of emodin with lipid membranes of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) are experimentally investigated with different techniques. Our studies have considered the neutral form of emodin (EMH) and its anionic/deprotonated form (EM⁻), and their interaction with a more and less packed lipid membrane, DMPC at the gel and fluid phases, respectively. Though DSC results indicate that the two species, EMH and EM⁻, similarly disrupt the packing of DMPC bilayers, spin labels clearly show that EMH causes a stronger bilayer disruption, both in gel and fluid DMPC. Fluorescence spectroscopy shows that both EMH and EM⁻ have a high affinity for DMPC: the binding of EM⁻ to both gel and fluid DMPC bilayers was found to be quite similar, and similar to that of EMH to gel DMPC, <em>K</em>_p = (1.4 ± 0.3)<em>x</em>10³. However, EMH was found to bind twice more strongly to fluid DMPC bilayers, <em>K</em>_p = (3.2 ± 0.3)<em>x</em>10³. Spin labels and optical absorption spectroscopy indicate that emodin is located close to the lipid bilayer surface, and suggest that EM⁻ is closer to the lipid/water interface than EMH, as expected. The present studies present a relevant contribution to the current understanding of the effect the two species of emodin, EMH and EM⁻, present on different microregions of an organism, as local <em>pH</em> values can vary significantly, can cause in a neutral lipid membrane, either more or less packed, liked gel and fluid DMPC, respectively, and could be extended to lipid domains of biological membranes.</p></div>","PeriodicalId":8979,"journal":{"name":"Biophysical chemistry","volume":"309 ","pages":"Article 107233"},"PeriodicalIF":3.8,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140347563","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}