Multistep Conformation Selection in Amyloid Assembly.
Ontology highlight
ABSTRACT:
SUBMITTER: Hsieh MC
PROVIDER: S-EPMC5709775 | biostudies-literature | 2017 Nov
REPOSITORIES: biostudies-literature
Publications
Multistep Conformation Selection in Amyloid Assembly.
Hsieh Ming-Chien MC Liang Chen C Mehta Anil K AK Lynn David G DG Grover Martha A MA
Journal of the American Chemical Society 20171115 47
Defining pathways for amyloid assembly could impact therapeutic strategies for as many as 50 disease states. Here we show that amyloid assembly is subject to different forces regulating nucleation and propagation steps and provide evidence that the more global β-sheet/β-sheet facial complementarity is a critical determinant for amyloid nucleation and structural selection. ...[more]
Similar Datasets
Project description:Graphene molecules, hexafluorotribenzo[a,g,m]coronene with n-carbon alkyl chains (FTBC-Cn, n = 4, 6, 8, 12) and Janus-type "double-concave" conformation, are used to fabricate self-assembly on highly oriented pyrolytic graphite surface. The structural dependence of the self-assemblies with molecular conformation and alkyl chain is investigated by scanning tunneling microscopy and density functional theory calculation. An interesting reverse face "up-down" way is observed in FTBC-C4 assembly due to the existence of hydrogen bonds. With the increase of the alkyl chain length and consequently stronger van der Waals interaction, the molecules no longer take alternating "up-down" orientation in their self-assembly and organize into various adlayers with lamellar, hexagonal honeycomb, and pseudohoneycomb structures based on the balance between intermolecular and molecule-substrate interactions. The results demonstrate that the featured "double-concave" molecules are available block for designing graphene nanopattern. From the results of scanning tunneling spectroscopy measurement, it is found that the electronic property of the featured graphene molecules is preserved when they are adsorbed on solid surface.
| S-EPMC2579342 | biostudies-literature
Project description:The eukaryotic chaperonin CCT (chaperonin containing TCP-1) uses cavities built into its double-ring structure to encapsulate and to assist folding of a large subset of proteins. CCT can inhibit amyloid fibre assembly and toxicity of the polyQ extended mutant of huntingtin, the protein responsible for Huntington's disease. This raises the possibility that CCT modulates other amyloidopathies, a still-unaddressed question. We show here that CCT inhibits amyloid fibre assembly of ?-synuclein A53T, one of the mutants responsible for Parkinson's disease. We evaluated fibrillation blockade in ?-synuclein A53T deletion mutants and CCT interactions of full-length A53T in distinct oligomeric states to define an inhibition mechanism specific for ?-synuclein. CCT interferes with fibre assembly by interaction of its CCT? and CCT? subunits with the A53T central hydrophobic region (NAC). This interaction is specific to NAC conformation, as it is produced once soluble ?-synuclein A53T oligomers form and blocks the reaction before fibres begin to grow. Finally, we show that this association inhibits ?-synuclein A53T oligomer toxicity in neuroblastoma cells. In summary, our results and those for huntingtin suggest that CCT is a general modulator of amyloidogenesis via a specific mechanism.
| S-EPMC5244355 | biostudies-literature
Project description:A series of simple hierarchical self-assembly steps achieve self-organization from the centimeter to the subnanometer-length scales in the form of square-centimeter arrays of linear nanopores, each one having a single chiral helical nanofilament of large internal surface area and interfacial interactions based on chiral crystalline molecular arrangements.
| S-EPMC4209994 | biostudies-literature
Project description:SMC (structural maintenance of chromosomes) family members play essential roles in chromosome condensation, sister chromatid cohesion and DNA repair. It remains unclear how SMCs structure chromosomes and how their mechanochemical cycle regulates their interactions with DNA. Here we used single-molecule fluorescence microscopy to visualize how Bacillus subtilis SMC (BsSMC) interacts with flow-stretched DNAs. We report that BsSMC can slide on DNA, switching between static binding and diffusion. At higher concentrations, BsSMCs form clusters that condense DNA in a weakly ATP-dependent manner. ATP increases the apparent cooperativity of DNA condensation, demonstrating that BsSMC can interact cooperatively through their ATPase head domains. Consistent with these results, ATPase mutants compact DNA more slowly than wild-type BsSMC in the presence of ATP. Our results suggest that transiently static BsSMC molecules can nucleate the formation of clusters that act to locally condense the chromosome while forming long-range DNA bridges.
| S-EPMC4725763 | biostudies-other
Project description:For several different proteins an apparent correlation has been observed between the propensity for dimerization by domain-swapping and the ability to aggregate into amyloid-like fibrils. Examples include the disease-related proteins ? 2-microglobulin and transthyretin. This has led to proposals that the amyloid-formation pathway may feature extensive domain swapping. One possible consequence of such an aggregation pathway is that the resulting fibrils would incorporate structural elements that resemble the domain-swapped forms of the protein and, thus, reflect certain native-like structures or domain-interactions. In magic angle spinning solid-state NMR-based and other structural studies of such amyloid fibrils, it appears that many of these proteins form fibrils that are not native-like. Several fibrils, instead, have an in-register, parallel conformation, which is a common amyloid structural motif and is seen, for instance, in various prion fibrils. Such a lack of native structure in the fibrils suggests that the apparent connection between domain-swapping ability and amyloid-formation may be more subtle or complex than may be presumed at first glance.
| S-EPMC3399535 | biostudies-literature
Project description:The assembly of individual molecules into hierarchical structures is a promising strategy for developing three-dimensional materials with properties arising from interaction between the individual building blocks. Virus capsids are elegant examples of biomolecular nanostructures, which are themselves hierarchically assembled from a limited number of protein subunits. Here, we demonstrate the bio-inspired modular construction of materials with two levels of hierarchy: the formation of catalytically active individual virus-like particles (VLPs) through directed self-assembly of capsid subunits with enzyme encapsulation, and the assembly of these VLP building blocks into three-dimensional arrays. The structure of the assembled arrays was successfully altered from an amorphous aggregate to an ordered structure, with a face-centered cubic lattice, by modifying the exterior surface of the VLP without changing its overall morphology, to modulate interparticle interactions. The assembly behavior and resultant lattice structure was a consequence of interparticle interaction between exterior surfaces of individual particles and thus independent of the enzyme cargos encapsulated within the VLPs. These superlattice materials, composed of two populations of enzyme-packaged VLP modules, retained the coupled catalytic activity in a two-step reaction for isobutanol synthesis. This study demonstrates a significant step toward the bottom-up fabrication of functional superlattice materials using a self-assembly process across multiple length scales and exhibits properties and function that arise from the interaction between individual building blocks.
| S-EPMC5870838 | biostudies-literature
Project description:The SH3 domain of the PI3 kinase (PI3-SH3 or PI3K-SH3) readily aggregates into fibrils in vitro and has served as an important model system in the investigation of the molecular properties and mechanism of formation of amyloid fibrils. We describe the molecular conformation of PI3-SH3 in amyloid fibril form as revealed by magic-angle spinning (MAS) solid-state nuclear magnetic resonance (NMR) spectroscopy. The MAS NMR spectra of these fibrils display excellent resolution, with narrow (13)C and (15)N line widths, representing a high degree of structural order and the absence of extensive molecular motion for the majority of the polypeptide chain. We have identified the spin systems of 82 of the 86 residues in the protein and obtained sequential resonance assignments for 75 of them. Chemical shift analysis indicates that the protein subunits making up the fibril adopt a compact conformation consisting of four well-defined beta-sheet regions and four random-coil elements with varying degrees of local dynamics or disorder. The backbone conformation of PI3-SH3 in fibril form differs significantly from that of the native state of the protein, both in secondary structure and in the location of dynamic or disordered segments. The site-specific MAS NMR analysis of PI3-SH3 fibrils we report here is compared with previously published mechanistic and structural data, resulting in a detailed interpretation of the factors that mediate fibril formation by PI3-SH3 and allowing us to propose a possible model of the core structure of the fibrils. Our results confirm the structural similarities between PI3-SH3 fibrils and amyloid assemblies directly related to degenerative and infectious diseases.
| S-EPMC2932965 | biostudies-literature
Project description:Amyloid formation is associated with devastating diseases such as Alzheimer's, Parkinson's and Type-2 diabetes. The large amyloid deposits found in patients suffering from these diseases have remained difficult to probe by structural means. Recent NMR models also predict heterotypic interactions from distinct peptide fragments but limited evidence of heterotypic packed sheets is observed in solution. Here we characterize two segments of the protein amyloid ? (A?) known to form fibrils in Alzheimer's disease patients. We designed two variants of A?(19-24) and A?(27-32), IFAEDV (I6V) and NKGAIF (N6F) to lower the aggregation propensity of individual peptides while maintaining the similar interactions between the two segments in their native forms. We found that the variants do not form significant amyloid fibrils individually but a 1:1 mixture forms abundant fibrils. Using ion mobility-mass spectrometry (IM-MS), hetero-oligomers up to decamers were found in the mixture while the individual peptides formed primarily dimers and some tetramers consistent with a strong heterotypic interaction between the two segments. We showed by X-ray crystallography that I6V formed a Class 7 zipper with a weakly packed pair of ?-sheets and no segregated dry interface, while N6F formed a more stable Class 1 zipper. In a mixture of equimolar N6F:I6V, I6V forms a more stable zipper than in I6V alone while no N6F or hetero-typic zippers are observed. These data are consistent with a mechanism where N6F catalyzes assembly of I6V into a stable zipper and perhaps into stable, pure I6V fibrils that are observed in AFM measurements.
| S-EPMC6032360 | biostudies-literature
Project description:The central dogma of the action of current anticancer drugs is that the drug tightly binds to its molecular target for inhibition. The reliance on tight ligand-receptor binding, however, is also the major root of drug resistance in cancer therapy. In this article, we highlight enzyme-instructed self-assembly (EISA)-the integration of enzymatic transformation and molecular self-assembly-as a multistep process for the development of cancer therapy. Using apoptosis as an example, we illustrate that the combination of enzymatic transformation and self-assembly, in fact, is an inherent feature of apoptosis. After the introduction of EISA of small molecules in the context of supramolecular hydrogelation, we describe several key studies to underscore the promises of EISA for developing cancer therapy. Particularly, we will highlight that EISA allows one to develop approaches to target "undruggable" targets or "untargetable" features of cancer cells and provides the opportunity for simultaneously interacting with multiple targets. We envision that EISA, used separately or in combination with current anticancer therapeutics, will ultimately lead to a paradigm shift for developing anticancer medicine that inhibit multiple hallmark capabilities of cancer.
| S-EPMC4533114 | biostudies-other
Project description:We engineered and employed a chaperone-like amyloid-binding protein Nucleobindin 1 (NUCB1) to stabilize human islet amyloid polypeptide (hIAPP) protofibrils for use as immunogen in mice. We obtained multiple monoclonal antibody (mAb) clones that were reactive against hIAPP protofibrils. A secondary screen was carried out to identify clones that cross-reacted with amyloid beta-peptide (A?42) protofibrils, but not with A?40 monomers. These mAbs were further characterized in several in vitro assays, in immunohistological studies of a mouse model of Alzheimer's disease (AD) and in AD patient brain tissue. We show that mAbs obtained by immunizing mice with the NUCB1-hIAPP complex cross-react with A?42, specifically targeting protofibrils and inhibiting their further aggregation. In line with conformation-specific binding, the mAbs appear to react with an intracellular antigen in diseased tissue, but not with amyloid plaques. We hypothesize that the mAbs we describe here recognize a secondary or quaternary structural epitope that is common to multiple amyloid protofibrils. In summary, we report a method to create mAbs that are conformation-sensitive and sequence-independent and can target more than one type of protofibril species.
| S-EPMC6378190 | biostudies-literature