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1.
The heat shock protein 90α (HSP90α) provides a promising molecular target for cancer therapy. A series of novel benzolactam inhibitors exhibited distinct inhibitory activity for HSP90α. However, the structural basis for the impact of distinct R1 substituent groups of nine benzolactam inhibitors on HSP90α binding affinities remains unknown. In this study, we carried out molecular docking, molecular dynamics (MD) simulations, and molecular mechanics and generalized Born/surface area (MM–GBSA) binding free energy calculations to address the differences. Molecular docking studies indicated that all nine compounds presented one conformation in the ATP-binding site of HSP90α N-terminal domain. MD simulations and subsequent MM–GBSA calculations revealed that the hydrophobic interactions between all compounds and HSP90α contributed the most to the binding affinity and a good linear correlation was obtained between the calculated and the experimental binding free energies (R = 0.88). The per residue decomposition revealed that the most remarkable differences of residue contributions were found in the residues Ala55, Ile96, and Leu107 defining a hydrophobic pocket for the R1 group, consistent with the analysis of binding modes. This study may be helpful for the future design of novel HSP90α inhibitors. 相似文献
2.
Hassanisadi M Barzegar A Yousefi R Dalgalarrondo M Chobert JM Haertlé T Saboury AA Moosavi-Movahedi AA 《Analytica chimica acta》2008,613(1):40-47
Molecular chaperones interact preferentially with certain aggregation-prone intermediates of target protein molecules. An estimation of the chaperone activity based on suppression of aggregation is required to be mechanistically understood. In this study, the multivariate curve resolution chemometric technique was applied on horse alcohol dehydrogenase (ADH) UV-spectra under thermal stress, to obtain the required information about the number and change in concentrations of the species involved. Chemometric analysis of UV-absorption spectra of horse ADH under thermal stress, led to the existence of three different molecular species including native (N), aggregation-prone intermediate (I) and final aggregate (A) species. Appearance and buildup of two molecular species I and A were connected to the disappearance of N-species. In the presence of β-caseins (BCN), however, a new complex between I and BCN (I-BCN) was formed. Meanwhile, by accretion of concentration of I-BCN complex, the light scattering intensity diminished. The data presented in this study clearly demonstrate that the interaction of BCN as a chaperone molecule with I-species takes place in a temperature-dependent manner and leads to a reversible I-BCN complex. In the absence of chaperones, I-state is subsequently converted to the final aggregate species. In the presence of BCN, this molecular species could be converted to the final aggregate state and/or form the I-BCN complex. 相似文献
3.
Tessa Sinnige 《Chemical science》2022,13(24):7080
Fibrillar protein aggregation is a hallmark of a variety of human diseases. Examples include the deposition of amyloid-β and tau in Alzheimer''s disease, and that of α-synuclein in Parkinson''s disease. The molecular mechanisms by which soluble proteins form amyloid fibrils have been extensively studied in the test tube. These investigations have revealed the microscopic steps underlying amyloid formation, and the role of factors such as chaperones that modulate these processes. This perspective explores the question to what extent the mechanisms of amyloid formation elucidated in vitro apply to human disease. The answer is not yet clear, and may differ depending on the protein and the associated disease. Nevertheless, there are striking qualitative similarities between the aggregation behaviour of proteins in vitro and the development of the related diseases. Limited quantitative data obtained in model organisms such as Caenorhabditis elegans support the notion that aggregation mechanisms in vivo can be interpreted using the same biophysical principles established in vitro. These results may however be biased by the high overexpression levels typically used in animal models of protein aggregation diseases. Molecular chaperones have been found to suppress protein aggregation in animal models, but their mechanisms of action have not yet been quantitatively analysed. Several mechanisms are proposed by which the decline of protein quality control with organismal age, but also the intrinsic nature of the aggregation process may contribute to the kinetics of protein aggregation observed in human disease.The molecular mechanisms of amyloid formation have been studied extensively in test tube reactions. This perspective article addresses the question to what extent these mechanisms apply to the complex situation in living cells and organisms. 相似文献
4.
You-Lin Xue Qiaoshi Zhang Yuna Sun Xiaohong Zhou Ian P. Hurley Gary W. Jones Youtao Song 《Journal of computer-aided molecular design》2018,32(11):1217-1227
Genetics experiments have identified six mutations located in the subdomain IA (A17V, R23H, G32D, G32S, R34K, V372I) of Ssa1 that influence propagation of the yeast [PSI+] prion. However, the underlining molecular mechanisms of these mutations are still unclear. The six mutation sites are present in the IA subdomain of the nucleotide-binding domain (NBD). The ATPase subdomain IA is a critical mediator of inter-domain allostery in Hsp70 molecular chaperones, so the mutation and changes in this subdomain may influence the function of the substrate-binding domain. In addition, ADP release is a rate-limiting step of the ATPase cycle and dysregulation of the ATPase cycle influences the propagation of the yeast [PSI+] prion. In this work, steered molecular dynamics (SMD) simulations were performed to explore the interaction between ADP and NBD. Results suggest that during the SMD simulations, hydrophobic interactions are predominant and variations in the binding state of ADP within the mutants is a potential reason for in vivo effects on yeast [PSI+] prion propagation. Additionally, we identify the primary residues in the ATPase domain that directly constitute the main hydrophobic interaction network and directly influence the ADP interaction state with the NBD of Ssa1. Furthermore, this in silico analysis reaffirms the importance of previously experimentally-determined residues in the Hsp70 ATPase domain involved in ADP binding and also identifies new residues potentially involved in this process. 相似文献
5.
Fumio Hamada Miyuki Narita Akira Makabe Hideaki Itoh 《Journal of inclusion phenomena and macrocyclic chemistry》2001,40(1-2):83-88
The effect of dansyl modified -cyclodextrin (1)on the chaperone activity of heat shock proteins such as HSP70 and HSP90 hasbeen studied. The fluorescence intensity of 1 was decreased when HSP70 and HSP90 were added to the host solution. This phenomenon suggested that host–guest complexation was occuring. The binding constants of 1 were obtained using a 1:1 complex formation type equation by employing the guest-induced fluorescence variations. Host 1 exhibited a higher binding ability forHSP70 than for HSP90. The effects of 1 on the chaperone activity and degradation of HSP70 and HSP90 were studied by measuring the absorption of aggregation of citrate synthase (C.S.) and sodium dodecyl sulfate (SDS)polyacrylamide gel electrophoresis of trypsin degradation, respectively. Host1 can contribute to regulate C.S. aggregation andpromote trypsin degradation of HSP70 and HSP90. 相似文献
6.
Differential expression of molecular chaperones in brain of patients with Down syndrome 总被引:2,自引:0,他引:2
Yoo BC Vlkolinsky R Engidawork E Cairns N Fountoulakis M Lubec G 《Electrophoresis》2001,22(6):1233-1241
Heat shock proteins (HSPs) in their molecular capacity as chaperones have been reported to regulate the apoptotic pathway and also play a critical role in protein conformational diseases such as Alzheimer's disease (AD). As all Down syndrome (DS) brains display AD-like neuropathology, neuronal loss in DS was shown to be mediated by apoptosis. We decided to investigate the expression patterns of HSPs in seven brain regions of adults with DS using two-dimensional polyacrylamide gel electrophoresis (2-DE). Following 2-DE, approximately 120 protein spots were successfully identified by matrix-assisted laser desorption/ionization--mass spectrometry (MALDI-MS) followed by quantification of the identified proteins. We unambiguously identified and quantified nine different chaperone proteins. Accordingly, all but three chaperone proteins did exhibit a significant change in expression. HSP 70 RY, heat shock cognate (HSC) 71 and glucose-regulated protein (GRP) 75 showed a significant decrease (P < 0.05) in DS temporal cortex whereas HSP 70.1 and GRP 78 were significantly increased (P<0.05) in cerebellum. Whilst T-complex 1 (TCP-1) epsilon subunit showed a significant decrease (P< 0.05) in parietal cortex, a similar extent of increase (P<0.05) as that observed in cerebellum was obtained in parietal levels of GRP 78. Alpha-crystallin B, HSP 60 and GRP 94 did not show any detectable changes in expression patterns. This report presents the first approach to quantify nine different chaperones simultaneously at the protein level in different brain regions and provides evidence for aberrant chaperone expression patterns in DS. The relevance of this aberrant expression patterns are discussed in relation to the biochemical and neuropathological abnormalities in DS brain. 相似文献
7.
Mj HSP16.5 is a small heat shock protein (sHSP) from the hyperthermophilic methanoarchaeon, Methanococcus jannaschii (Mj), which lives at the environment of high temperature up to 94 °C. The structural data showed that Mj HSP16.5 was a 24-mer that formed a hollow sphere with octahedral symmetry. Mj HSP16.5 was very stable at pH 7 that it maintained the 24-mer structure even at 85 °C. In the present study, we investigated the unfolding process of Mj HSP16.5 in the presence of denaturants using several techniques, including circular dichroism (CD), dynamic light scattering (DLS), fluorescence spectroscopy, and size exclusive chromatography (SEC). We found that 8 mol·L−1 urea had no obvious effect on the structure of Mj HSP16.5 at pH 7. The unfolding of Mj HSP16.5 at pH 7 in the presence of guanidine hydrochloride (GdHCl) showed hierarchical behavior. Three significant transitions were observed around 2.0, 3.0, and 6.0 mol·L−1 GdHCl at pH 7. ANS (8-anilino-1- naphthalenesulfonic acid) titration results showed that the binding ability of Mj HSP16.5 to ANS decreased gradually as the concentration of GdHCl increased until around 2.0 mol·L−1 GdHCl, indicating surface hydrophobic area change, and this first transition was companioned with precipitation of Mj HSP16.5. Acrylamide quenching of fluorescence showed that the Stern-Volmer constant changed at about 3.0 mol·L−1 GdHCl, indicating changes of the dimeric interface, and this phase transition was companioned with oligomeric state change from 24-mer to small oligomers (4-mer to 8-mer). The last unfolding phase started around 5.0 mol·L−1 GdHCl, with a midpoint of 6.1 mol·L−1 GdHCl, and Mj HSP16.5 was completely unfolded at 7.0 mol·L−1 GdHCl. We also found that Mj HSP16.5 could be quite easily unfolded at pH 3, where it could be completely unfolded in 4.0 mol·L−1 GdHCl. 相似文献
8.
This work describes the hydrophobic interaction chromatography of homo-deoxyoligonucleotides polyA, polyT and polyU with sizes up to 30 bases on a Sepharose gel derivatized with the 1,4-butanediol diglycidyl ether. The oligonucleotides interacted differently with the column according to the molecular mass, the hydrophobic character of the individual bases, the secondary structure of the molecule and the concentration of ammonium sulphate in the eluent. The retention factor, k', was determined from the chromatographic profiles at different concentrations of ammonium sulphate. A linear relationship between log k' and the concentration of ammonium sulphate in the eluent was found for all oligonucleotides at the higher concentrations (> 1.0 M) of ammonium sulphate. The slope of these plots, termed the hydrophobic interaction parameter, was found to be an increasing function of the number of nucleotides. The same plots reveal that polyA molecules with high molecular mass have lower retention factors when compared with polyT, an observation that was not expected since the hydrophobicity of adenine is higher than that of thymine. This behaviour was due to the existence of secondary structures in polyA, which decrease the exposed hydrophobic area of the molecule. 相似文献
9.
Small heat shock proteins (sHSPs) exist ubiquitously among all organisms, with a variety of functions. All small heat shock
proteins assemble into a native large oligomeric state containing 9–40 monomers. The sHSPs show chaperone-like activity to
prevent the aggregation of nonnative proteins under stressful cellular conditions such as non-optimal temperatures, pH changes,
osmotic pressure, and exposure to toxic chemicals. It was found that a common dimeric subunit of sHSPs might be the major
active species, but whether the native large oligomeric state is only a storage state or a state crucial to its molecular
chaperone activity is still under debate. The native large oligomeric state of the small heat shock protein from a hyperthermophilic
methanarchaeon, Methanococcus jannaschii (Mj HSP 16.5), is a stable icositetramer, which is a symmetric hollow sphere that is very stable even at 85°C, and no small
active subunit has been detected till now. Our results show that Mj sHSP 16.5 changes into small and active oligomeric state
at pH 3, likely as octamers (average result) at 25°C, and dimers at 65°C. The dimer of Mj HSP 16.5 at pH 3.0 and 65°C is very
active and efficient, even 7-fold more efficient than the high-temperature-activated icositetramer at neutral pH. Monomer
exchange can be observed between dimers of Mj HSP 16.5 at pH 3.0 and 65°C. These results not only demonstrate that the icositetramer
structure of Mj sHSP16.5 is not necessary for its molecular chaperone activity, but also suggest that Mj sHSP16.5 is a very
efficient chaperone acting at high temperature and under the acidic condition. Even though it is not clear whether the native
environment of Methanococcus jannaschii is acidic or not, given its ability to excrete acidic compounds, it is likely that Methanococcus jannaschii will encounter acidic internal or external environments at high temperature. Our results demonstrate that Mj HSP 16.5 may
help Methanococcus jannaschii to survive better under those extreme environmental conditions.
Supported by the National Natural Science Foundation of China (Grant Nos. 20203001, 20673003, and 30490245) and Ministry of
Science and Technology of China (Grant No. 2006AA02Z301) 相似文献
10.
Heat shock protein 70 is an effective anticancer target as it influences many signaling pathways. Hence the study investigated the important pharmacophore feature required for ATPase inhibitors of HSP70 by generating a ligand based pharmacophore model followed by virtual based screening and subsequent validation by molecular docking in Discovery studio V4.0. The most extrapolative pharmacophore model (hypotheses 8) consisted of four hydrogen bond acceptors. Further validation by external test set prediction identified 200 hits from Mini Maybridge, Drug Diverse, SCPDB compounds and Phytochemicals. Consequently, the screened compounds were refined by rule of five, ADMET and molecular docking to retain the best competitive hits. Finally Phytochemical compounds Muricatetrocin B, Diacetylphiladelphicalactone C, Eleutheroside B and 5-(3-{[1-(benzylsulfonyl)piperidin-4-yl]amino}phenyl)- 4-bromo-3-(carboxymethoxy)thiophene-2-carboxylic acid were obtained as leads to inhibit the ATPase activity of HSP70 in our findings and thus can be proposed for further in vitro and in vivo evaluation. 相似文献
11.
A. Ebrahim-Habibi D. Morshedi N. Rezaei-Ghaleh M. Sabbaghian M. Nemat-Gorgani 《Journal of the Iranian Chemical Society》2010,7(3):521-544
Protein aggregates, whether amorphous or structured (amyloid), have attracted much attention in recent years and despite extensive efforts, the mechanism of their formation is poorly understood. While “natural” aggregation (polymerization) of monomers could improve the biological function of some proteins, it is usually the darker side of this phenomenon which is discussed in many studies: deleterious aggregation that could lead to loss of biological activity under in vitro conditions or cause misfolding diseases. In this review, protein aggregation has been overviewed, starting from some general concepts involved in its formation, followed by mentioning studies aimed at elucidation of its kinetics and mechanism, or characterization of intermediates that would be aggregation-prone, and finally, reporting some of the studies related to the design of methods that would control the process. Similarly, amyloid aggregates have been defined, and current methods used in their characterization have been briefly described, with an emphasis on in silico studies. Finally, identification and design of such molecules which may be effective in control of this process is discussed. 相似文献
12.
Suzanne OConnor Yann-Vaï Le Bihan Isaac M. Westwood Manjuan Liu Oi Wei Mak Gabriel Zazeri Ana P. R. Povinelli Alan M. Jones Rob van Montfort Jhannes Reynisson Ian Collins 《Molecules (Basel, Switzerland)》2022,27(3)
Heat Shock Protein 70s (HSP70s) are key molecular chaperones that are overexpressed in many cancers and often associated with metastasis and poor prognosis. It has proven difficult to develop ATP-competitive, drug-like small molecule inhibitors of HSP70s due to the flexible and hydrophilic nature of the HSP70 ATP-binding site and its high affinity for endogenous nucleotides. The aim of this study was to explore the potential for the inhibition of HSP70 through alternative binding sites using fragment-based approaches. A surface plasmon resonance (SPR) fragment screen designed to detect secondary binding sites in HSP70 led to the identification by X-ray crystallography of a cryptic binding site in the nucleotide-binding domain (NBD) of HSP70 adjacent to the ATP-binding site. Fragment binding was confirmed and characterized as ATP-competitive using SPR and ligand-observed NMR methods. Molecular dynamics simulations were applied to understand the interactions with the protein upon ligand binding, and local secondary structure changes consistent with interconversion between the observed crystal structures with and without the cryptic pocket were detected. A virtual high-throughput screen (vHTS) against the cryptic pocket was conducted, and five compounds with diverse chemical scaffolds were confirmed to bind to HSP70 with micromolar affinity by SPR. These results identified and characterized a new targetable site on HSP70. While targeting HSP70 remains challenging, the new site may provide opportunities to develop allosteric ATP-competitive inhibitors with differentiated physicochemical properties from current series. 相似文献
13.
14.
《Comptes Rendus Chimie》2003,6(8-10):903-910
This mini-account describes our recent effort to exploit dendritic phthalocyanines, focusing on their photophysical properties and aggregation behavior in water and in microheterogeneous media. Two series of dendritic phthalocyanines have been prepared. The ones with terminal ester functionalities are non-aggregated in common organic solvents, exhibiting an intramolecular singlet-singlet energy transfer from the excited aryl-containing dendrons to the phthalocyanine core. The other series contain terminal carboxylate groups of which the aggregation tendency in water decreases as the size of the dendron increases. The lower-generation analogues are susceptible to surfactants, in particular the cationic n-hexadecyltrimethylammonium bromide (CTAB), and poly(ethylene oxide) (PEO), which are very effective to disrupt the molecular aggregation of phthalocyanines. The interactions have been monitored by absorption and fluorescence spectroscopy together with laser light scattering. The photophysical properties of the dendrimer/PEO complexes have also been studied by transient spectroscopy. To cite this article: D.K.P. Ng, C. R. Chimie 6 (2003). 相似文献
15.
V Tiriveedhi KD Conzen J Liaw-Conlin G Upadhya J Malone RR Townsend R Kerns J Jia K Csontos S Ramachandran T Mohanakumar CD Anderson WC Chapman 《BMC biochemistry》2012,13(1):17-9
ABSTRACT: BACKGROUND: The molecular basis of the increased susceptibility of steatotic livers to warm ischemia/reperfusion (I/R) injury during transplantation remains undefined. Animal model for warm I/R injury was induced in obese Zucker rats. Lean Zucker rats provided controls. Two dimensional differential gel electrophoresis was performed with liver protein extracts. Protein features with significant abundance ratios (p < 0.01) between the two cohorts were selected and analyzed with HPLC/MS. Proteins were identified by Uniprot database. Interactive protein networks were generated using Ingenuity Pathway Analysis and GRANITE software. RESULTS: The relative abundance of 105 proteins was observed in warm I/R injury. Functional grouping revealed four categories of importance: molecular chaperones/endoplasmic reticulum (ER) stress, oxidative stress, metabolism, and cell structure. Hypoxia up-regulated 1, calcium binding protein 1, calreticulin, heat shock protein (HSP) 60, HSP-90, and protein disulfide isomerase 3 were chaperonins significantly (p < 0.01) down-regulated and only one chaperonin, HSP-1was significantly upregulated in steatotic liver following I/R. CONCLUSION: Down-regulation of the chaperones identified in this analysis may contribute to the increased ER stress and, consequently, apoptosis and necrosis. This study provides an initial platform for future investigation of the role of chaperones and therapeutic targets for increasing the viability of steatotic liver allografts. 相似文献
16.
G. Rajesh Krishnan Yuan Yuan Ayesha Arzumand Debanjan Sarkar 《Journal of polymer science. Part A, Polymer chemistry》2014,52(14):1917-1928
Poly(ethylene glycol) (PEG) end capped with biodegradable hydrophobic dipeptides shows versatile gelation behavior in a wide range of aqueous and organic solvents. This gelation characteristic is attributed to the aggregation of polymer chains induced by dipeptide end groups. Both PEG molecular weight and molecular structure of end groups control this aggregation by striking a balance between two opposing molecular interactions: solubility of the PEG segment which tends to dissolve the polymer while hydrophobic and intermolecular noncovalent interactions between the end groups induce aggregation. Morphologically, this aggregated structure forms interpenetrating nano sheets with characteristic microstructural features. These gels are biodegradable and possess physicomechanical characteristics suitable for biomedical applications. Furthermore, proteins and hydrophobic model drugs can be encapsulated within the gels from aqueous and organic solvents, respectively, and can be released in a controlled fashion which indicates the applicability of the gels as drug delivery vehicles. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 1917–1928 相似文献
17.
Finn L. Aachmann Kim L. Larsen Reinhard Wimmer 《Journal of inclusion phenomena and macrocyclic chemistry》2012,73(1-4):349-357
Cyclodextrins (CyD) have proven effects on the stability of proteins and can be used in the formulation of aggregation prone therapeutic proteins. This effect stems from specific interactions between the CyD (preferably β-CyD) and solvent exposed amino acid residues. Here the interaction with hydrophobic aromatic amino acid residues stands out and the interaction between CyDs and these amino acid residues holds the key to understanding the observed effects, which CyDs exerts on proteins and peptides. Here we present a comparative study of the interactions between free and peptide bound aromatic amino acids and their derivatives with α, β and γ-CyDs using NMR spectroscopy. We propose a novel, quantitative means of assessing the penetration depth of guest molecules in CyD cavities, the penetration gauge Π, and apply it to the observed interaction patterns from ROESY NMR spectra. We demonstrate that the penetration depths of the aromatic rings within the CyDs rely highly on the nature of the remainder of the guest molecule. Thus the presence of charges, neighboring amino acids and the specific positioning on the surface of a protein highly influences the penetration depth and geometry of guest–CyD interactions. 相似文献
18.
Kyoungsook Park Kyusam Choi Hyemee Kim Kwangbae Kim Mi Hee Lee Je-Ho Lee Jean Chinock Kim Rim 《Experimental & molecular medicine》2009,41(6):371-380
During carcinogenesis, NF-κB mediates processes associated with deregulation of the normal control of proliferation, angiogenesis, and metastasis. Thus, suppression of NF-κB has been linked with chemoprevention of cancer. Accumulating findings reveal that heat shock protein 90 (HSP90) is a molecular chaperone and a component of the IκB kinase (IKK) complex that plays a central role in NF-κB activation. HSP90 also stabilizes key proteins involved in cell cycle control and apoptosis signaling. We have determined whether the exogenous administration of isoflavone-deprived soy peptide prevents 7,12-dimethylbenz[α]anthracene (DMBA)-induced rat mammary tumorigenesis and investigated the mechanism of action. Dietary administration of soy peptide (3.3 g/rat/day) significantly reduced the incidence of ductal carcinomas (50%), the number of tumors per multiple tumor-bearing rats (49%; P < 0.05), and extended the latency period of tumor development (8.07 ± 0.92 weeks) compared to control diet animals (10.80 ± 1.30; P < 0.05). Our results have further demonstrated that soy peptide (1) dramatically inhibits the expression of HSP90, thereby suppressing signaling pathway leading to NF-κB activation; (2) induces expression of p21, p53, and caspase-3 proteins; and (3) inhibits expression of VEGF. In agreement with our in vivo data, soy peptide treatment inhibited the growth of human breast MCF-7 tumor cells in a dose-dependent manner and induced apoptosis. Taken together, our in vivo and in vitro results suggest chemopreventive and tumor suppressive functions of isoflavone-deprived soy peptide by inducing growth arrest and apoptosis. 相似文献
19.
Yulong Bai Wang Wan Yanan Huang Wenhan Jin Haochen Lyu Qiuxuan Xia Xuepeng Dong Zhenming Gao Yu Liu 《Chemical science》2021,12(24):8468
Co-aggregation of multiple pathogenic proteins is common in neurodegenerative diseases but deconvolution of such biochemical process is challenging. Herein, we developed a dual-color fluorogenic thermal shift assay to simultaneously report on the aggregation of two different proteins and quantitatively study their thermodynamic stability during co-aggregation. Expansion of spectral coverage was first achieved by developing multi-color fluorogenic protein aggregation sensors. Orthogonal detection was enabled by conjugating sensors of minimal fluorescence crosstalk to two different proteins via sortase-tag technology. Using this assay, we quantified shifts in melting temperatures in a heterozygous model protein system, revealing that the thermodynamic stability of wild-type proteins was significantly compromised by the mutant ones but not vice versa. We also examined how small molecule ligands selectively and differentially interfere with such interplay. Finally, we demonstrated these sensors are suited to visualize how different proteins exert influence on each other upon their co-aggregation in live cells.A little leak will sink a great ship! We prepared a series of multi-color protein aggregation sensors and developed a dual-color thermal shift assay to simultaneously and quantitatively report on protein co-aggregation of two different proteins. 相似文献