bioRxiv - Biophysics最新文献_第8页

Faster amylin aggregation on fibrillar collagen hastens diabetic progression through β cell death and loss of function 淀粉样蛋白在纤维胶原上的快速聚集会导致β细胞死亡和功能丧失，从而加速糖尿病的进程

bioRxiv - Biophysics Pub Date : 2024-08-11 DOI: 10.1101/2024.08.10.607320

Md Asrafuddoza Hazari, Gautam Kannan, Akash Kumar Jha, Musale Krushna Pavan, Subrata Dasgupta, Farhin Sultana, Soumya Ranjan Pujahari, Simran Singh, Sarbajeet Dutta, Sai Prasad Pydi, Sankhadeep Dutta, Prasenjit Bhaumik, Hamim Zafar, Ashutosh Kumar, Shamik Sen

{"title":"Faster amylin aggregation on fibrillar collagen hastens diabetic progression through β cell death and loss of function","authors":"Md Asrafuddoza Hazari, Gautam Kannan, Akash Kumar Jha, Musale Krushna Pavan, Subrata Dasgupta, Farhin Sultana, Soumya Ranjan Pujahari, Simran Singh, Sarbajeet Dutta, Sai Prasad Pydi, Sankhadeep Dutta, Prasenjit Bhaumik, Hamim Zafar, Ashutosh Kumar, Shamik Sen","doi":"10.1101/2024.08.10.607320","DOIUrl":"https://doi.org/10.1101/2024.08.10.607320","url":null,"abstract":"Amyloid deposition of the neuroendocrine peptide amylin in islet tissues is a hallmark of type 2 diabetes (T2DM), leading to beta cell toxicity through nutrient deprivation, membrane rupture and apoptosis. Though accumulation of toxic amylin aggregates in islet matrices is well documented, the role of the islet extracellular matrix in mediating amylin aggregation and its pathological consequences remains elusive. Here, we address this question by probing amylin interaction with collagen I (Col I) whose expression in the islet tissue increases during diabetes progression. By combining multiple biophysical techniques, we show that hydrophobic, hydrophilic & cation-pi interactions regulate amylin binding to Col I, with fibrillar collagen driving faster amylin aggregation. Amylin-entangled Col I matrices containing high amounts of amylin induce death and loss of function of INS1E beta-cells. Together, our results illustrate how amylin incorporation in islet matrices through amylin-Col interactions drives T2DM progression by impacting beta-cell viability and insulin secretion.","PeriodicalId":501048,"journal":{"name":"bioRxiv - Biophysics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141945057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Oligomerization-Mediated Phase-Separation in the Nucleoid-Associated Sensory Protein H-NS is Controlled by Ambient Cues 核糖体相关感官蛋白 H-NS 的寡聚化--介导的相分离受环境线索控制

bioRxiv - Biophysics Pub Date : 2024-08-11 DOI: 10.1101/2024.08.10.607472

Bincy Lukose, Saloni Goyal, Athi N Naganathan

{"title":"Oligomerization-Mediated Phase-Separation in the Nucleoid-Associated Sensory Protein H-NS is Controlled by Ambient Cues","authors":"Bincy Lukose, Saloni Goyal, Athi N Naganathan","doi":"10.1101/2024.08.10.607472","DOIUrl":"https://doi.org/10.1101/2024.08.10.607472","url":null,"abstract":"H-NS, a nucleoid-associated protein (NAP) from enterobacteria, regulates gene expression by dynamically transducing environmental cues to conformational assembly and DNA binding. In this work, we show that H-NS from Escherichia coli, which can assemble into octameric and tetrameric oligomerization states, forms spontaneous micron-sized liquid-like condensates with DNA at sub-physiological concentrations in vitro. The heterotypic condensates are metastable at 298 K, partially solubilizing with time, while still retaining their liquid-like properties. The condensates display UCST-like phase behavior solubilizing at higher temperatures, but with a large decrease in droplet-assembly propensities at 310 K and also at higher ionic strength. Condensate formation can be tuned in a cyclic manner between 298 and 310 K with the extent of reversibility determined by the incubation time, highlighting strong hysteresis. An engineered phospho-mimetic variant (Y61E) of H-NS, which is dimeric and only weakly binds DNA, is unable to form condensates. The Y61E mutant solubilizes pre-formed H-NS condensates with DNA in a few minutes with nearly an order of magnitude speed-up in droplet dissolution at 310 K relative to 298 K, demonstrating rapid molecular transport between dilute and condensed phases. Our results establish that the oligomerization of H-NS is intrinsically tied not only to DNA binding but also its phase-separation tendencies, while showcasing the regulatable and programmable nature of heterotypic condensates formed by an archetypal NAP via multiple cues and their lifetimes.","PeriodicalId":501048,"journal":{"name":"bioRxiv - Biophysics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141945054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Quantitative comparison of the structural differences between NRAS and its mutations by well-tempered metadynamics simulations 通过温差元动力学模拟定量比较 NRAS 及其突变体之间的结构差异

bioRxiv - Biophysics Pub Date : 2024-08-10 DOI: 10.1101/2024.08.09.607354

Zheyao Hu, Jordi Marti

引用次数: 0

Different folding mechanisms in prion proteins from mammals with different disease susceptibility observed at the single-molecule level 在单分子水平上观察到哺乳动物朊病毒蛋白的不同折叠机制与不同的疾病易感性

bioRxiv - Biophysics Pub Date : 2024-08-10 DOI: 10.1101/2024.08.09.607387

Uttam Anand, Shubhadeep Patra, Rohith Vedhthaanth Sekar, Craig R Garen, Michael T Woodside

{"title":"Different folding mechanisms in prion proteins from mammals with different disease susceptibility observed at the single-molecule level","authors":"Uttam Anand, Shubhadeep Patra, Rohith Vedhthaanth Sekar, Craig R Garen, Michael T Woodside","doi":"10.1101/2024.08.09.607387","DOIUrl":"https://doi.org/10.1101/2024.08.09.607387","url":null,"abstract":"Misfolding of the protein PrP causes prion diseases in mammals. Disease susceptibility varies widely among species, despite PrP sequences differing by only a few amino acids. How these differences alter PrP folding and misfolding remains unclear. We compared the folding dynamics of single PrP molecules from three species with different disease susceptibility: dogs (immune), hamsters (susceptible), and bank voles (extremely susceptible). Measurements with optical tweezers revealed important differences between the folding cooperativity, pathways, energy barriers, and kinetics of these proteins. In contrast to the two-state folding of hamster PrP, dog PrP always folded through multiple intermediates. However, both featured rapid native folding, homogeneous energy barriers, and no readily observable misfolding. Bank vole PrP also folded via intermediates, but more slowly and via inhomogeneous barriers. Most notably, it formed several metastable misfolded states starting from the unfolded state. Analyzing the sequence of intermediates seen in pulling curves, we found significant differences in the folding pathways for dog and bank vole PrP, implying that sequence mutations altered energy barriers so as to redirect folding pathways. These results show that subtle differences in PrP sequence between species produce profound changes in folding behavior, providing insight into the factors underlying misfolding propensity.","PeriodicalId":501048,"journal":{"name":"bioRxiv - Biophysics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141945058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Heterogenous organization in condensates of multiple transcription factors in embryonic stem cells 胚胎干细胞中多种转录因子凝聚体的异质组织

bioRxiv - Biophysics Pub Date : 2024-08-10 DOI: 10.1101/2024.06.14.599027

Azuki Mizutani, Cheng Tan, Yuji Sugita, Shoji Takada

引用次数: 0

Auditory Cellular Cooperativity Probed Via Spontaneous Otoacoustic Emissions 通过自发声发射探测听觉细胞的合作性

bioRxiv - Biophysics Pub Date : 2024-08-10 DOI: 10.1101/2024.08.09.607375

Christopher Bergevin, Rebecca Whiley, Hero Wit, Geoffrey Manley, Pim van Dijk

{"title":"Auditory Cellular Cooperativity Probed Via Spontaneous Otoacoustic Emissions","authors":"Christopher Bergevin, Rebecca Whiley, Hero Wit, Geoffrey Manley, Pim van Dijk","doi":"10.1101/2024.08.09.607375","DOIUrl":"https://doi.org/10.1101/2024.08.09.607375","url":null,"abstract":"As a sound pressure detector that uses energy to boost both its sensitivity and selectivity, the inner ear is an active non-equilibrium system. The collective processes of the inner ear giving rise to this exquisite functionality remain poorly understood. One manifestation of the active ear across the animal kingdom is the presence of spontaneous otoacoustic emission (SOAE), idiosyncratic arrays of spectral peaks that can be measured using a sensitive microphone in the ear canal.1 Current SOAE models attempt to explain how multiple peaks arise, and generally assume a spatially-distributed tonotopic system. However, the nature of the generators, their coupling, and the role of noise (e.g., Brownian motion) are hotly debated, especially given the inner ear morphological diversity across vertebrates. One means of probing these facets of emission generation is studying fluctuations in SOAE peak properties, which produce amplitude (AM) and frequency modulations (FM). These properties are likely related to the presence of noise affecting active cellular generation elements, and the coupling between generators. To better biophysically constrain models, this study characterizes the fluctuations in filtered SOAE peak waveforms, focusing on interrelations within and across peaks. A systematic approach is taken, examining three species that exhibit disparate inner ear morphologies: humans, barn owls, and green anole lizards. To varying degrees across all three groups, SOAE peaks have intra- (IrP) and interpeak (IPP) correlations indicative of interactions between generative elements. Activity from anole lizards, whose auditory sensory organ is relatively much smaller than that of humans or barn owls, showed a much higher incidence of IPP correlations. Taken together, we propose that these data are indicative of SOAE cellular generators acting cooperatively, allowing the ear to function as an optimized detector.","PeriodicalId":501048,"journal":{"name":"bioRxiv - Biophysics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141945059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular dynamics simulations illuminate the role of sequence context in the ELF3-PrD-based temperature sensing mechanism in plants 分子动力学模拟揭示了序列上下文在植物基于 ELF3-PrD 的温度感应机制中的作用

bioRxiv - Biophysics Pub Date : 2024-08-10 DOI: 10.1101/2024.08.09.607385

Richard J Lindsay, Rafael Giordano Viegas, VITOR B P LEITE, Philip Anthony Wigge, Sonya M Hanson

{"title":"Molecular dynamics simulations illuminate the role of sequence context in the ELF3-PrD-based temperature sensing mechanism in plants","authors":"Richard J Lindsay, Rafael Giordano Viegas, VITOR B P LEITE, Philip Anthony Wigge, Sonya M Hanson","doi":"10.1101/2024.08.09.607385","DOIUrl":"https://doi.org/10.1101/2024.08.09.607385","url":null,"abstract":"The evening complex (EC) is a tripartite DNA repressor and a core component of the circadian clock that provides a mechanism for temperature-responsive growth and development of many plants. ELF3, a component of the EC, is a disordered scaffolding protein that blocks transcription of growth genes at low temperature. At increased temperature EC DNA binding is disrupted and ELF3 is sequestered in a reversible nuclear condensate, allowing transcription and growth to proceed. The condensation is driven by a low complexity prion-like domain (PrD), and the sensitivity of the temperature response is modulated by the length of a variable polyQ tract, with a longer polyQ tract corresponding to enhanced condensate formation and hypocotyl growth at increased temperature. Here, a series of computational studies provides evidence that polyQ tracts promote formation of temperature-sensitive helices in flanking residues with potential impacts for EC stability under increasing temperature. REST2 simulations uncover a heat-induced population of condensation-prone conformations that results from the exposure of 'sticky' aromatic residues by temperature-responsive breaking of long-range contacts. Coarse-grained Martini simulations reveal both polyQ tract length and sequence context modulate the temperature dependence of cluster formation. Understanding the molecular mechanism underlying the ELF3-PrD temperature response in plants has implications for technologies including modular temperature-response elements for heat-responsive protein design and agricultural advances to enable optimization of crop yields and allow plants to thrive in increasingly inhospitable environments.","PeriodicalId":501048,"journal":{"name":"bioRxiv - Biophysics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141945063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The SH Protein of Mumps Virus is a Druggable Pentameric Viroporin 腮腺炎病毒的 SH 蛋白是一种可药用的五聚体病毒蛋白

bioRxiv - Biophysics Pub Date : 2024-08-10 DOI: 10.1101/2024.08.09.607002

Kira Devantier, Trine L. Toft-Bertelsen, Andreas Prestel, Viktoria M. S. Kjaer, Cagla Sahin, Marco Giulini, Stavroula Louka, Katja Spiess, Asmita Manandhar, Katrine Qvortrup, Trond Ulven, Bo Hjorth Bentzen, Alexandre Bonvin, Nanna MacAulay, Birthe B. Kragelund, Mette M Rosenkilde

{"title":"The SH Protein of Mumps Virus is a Druggable Pentameric Viroporin","authors":"Kira Devantier, Trine L. Toft-Bertelsen, Andreas Prestel, Viktoria M. S. Kjaer, Cagla Sahin, Marco Giulini, Stavroula Louka, Katja Spiess, Asmita Manandhar, Katrine Qvortrup, Trond Ulven, Bo Hjorth Bentzen, Alexandre Bonvin, Nanna MacAulay, Birthe B. Kragelund, Mette M Rosenkilde","doi":"10.1101/2024.08.09.607002","DOIUrl":"https://doi.org/10.1101/2024.08.09.607002","url":null,"abstract":"Viral infections are on the rise and drugs targeting viral proteins are needed. Viroporins constitute a growing group of virus-encoded transmembrane oligomeric proteins that allow passage of small molecules across the membrane. Despite sparsity in viroporin structures, recent work has revealed diversity in both the number of transmembrane helices and oligomeric states. Here we provide evidence that the small hydrophobic protein (SH) from mumps virus is a pentameric viroporin. From extensive biophysical data, a HADDOCK model of full-length SH shows its intracellular C-terminal region to form an extended structure crucial to stabilization of the pentamer. Heterologous expression of wild type SH and variants in Xenopus laevis oocytes reveals the viroporin as a chloride channel, facilitated by conserved hydroxyl-carrying residues lining the pore. The channel function of SH is inhibited by the small-molecule BIT225, highlighting the potential for antiviral targeting through SH.","PeriodicalId":501048,"journal":{"name":"bioRxiv - Biophysics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141945060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Generating Multi-state Conformations of P-type ATPases with a Diffusion Model 用扩散模型生成 P 型 ATP 酶的多态构象

bioRxiv - Biophysics Pub Date : 2024-08-09 DOI: 10.1101/2024.08.07.607107

Jingtian Xu, Yong Wang

引用次数: 0

Structure and function of the human apoptotic scramblase Xkr4 人类凋亡扰乱酶 Xkr4 的结构和功能

bioRxiv - Biophysics Pub Date : 2024-08-09 DOI: 10.1101/2024.08.07.607004

Alessio Accardi, Sayan Chakraborty, Zhang Feng, Sangyun Lee, Omar E Alvarenga, Aniruddha Panda, Renato Bruni, George Khelashvili, Kallol Gupta

引用次数: 0