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1,752 results on '"Kay, Lewis E."'

1. Electrostatics of Salt-Dependent Reentrant Phase Behaviors Highlights Diverse Roles of ATP in Biomolecular Condensates

Author

Lin, Yi-Hsuan, Kim, Tae Hun, Das, Suman, Pal, Tanmoy, Wessén, Jonas, Rangadurai, Atul Kaushik, Kay, Lewis E., Forman-Kay, Julie D., and Chan, Hue Sun

Subjects
Quantitative Biology - Biomolecules
Abstract

Liquid-liquid phase separation (LLPS) involving intrinsically disordered protein regions (IDRs) is a major physical mechanism for biological membraneless compartmentalization. The multifaceted electrostatic effects in these biomolecular condensates are exemplified here by experimental and theoretical investigations of the different salt- and ATP-dependent LLPSs of an IDR of messenger RNA-regulating protein Caprin1 and its phosphorylated variant pY-Caprin1, exhibiting, e.g., reentrant behaviors in some instances but not others. Experimental data are rationalized by physical modeling using analytical theory, molecular dynamics, and polymer field-theoretic simulations, indicating in general that interchain salt bridges enhance LLPS of polyelectrolytes such as Caprin1 and that the high valency of ATP-magnesium is a significant factor for its colocalization with the condensed phases, as similar trends are observed for several other IDRs. Our findings underscore the role of biomolecular condensates in modulating ion concentrations and its functional ramifications., Comment: 67 pages, 2 main-text tables, 8 main-text figures, 6 supporting figures, 155 references. Submitted to eLife

Published
2024

2. Design of amyloidogenic peptide traps

Author

Sahtoe, Danny D., Andrzejewska, Ewa A., Han, Hannah L., Rennella, Enrico, Schneider, Matthias M., Meisl, Georg, Ahlrichs, Maggie, Decarreau, Justin, Nguyen, Hannah, Kang, Alex, Levine, Paul, Lamb, Mila, Li, Xinting, Bera, Asim K., Kay, Lewis E., Knowles, Tuomas P. J., and Baker, David

Published
2024
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5. Disrupting the α-synuclein-ESCRT interaction with a peptide inhibitor mitigates neurodegeneration in preclinical models of Parkinson’s disease

Author

Nim, Satra, O’Hara, Darren M., Corbi-Verge, Carles, Perez-Riba, Albert, Fujisawa, Kazuko, Kapadia, Minesh, Chau, Hien, Albanese, Federica, Pawar, Grishma, De Snoo, Mitchell L., Ngana, Sophie G., Kim, Jisun, El-Agnaf, Omar M. A., Rennella, Enrico, Kay, Lewis E., Kalia, Suneil K., Kalia, Lorraine V., and Kim, Philip M.

Published
2023
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29. Atomic resolution map of the solvent interactions driving SOD1 unfolding in CAPRIN1 condensates.

Author

Ahmed, Rashik, Mingyang Liang, Hudson, Rhea P., Rangadurai, Atul K., Shuya Kate Huang, Forman-Kay, Julie D., and Kay, Lewis E.

Subjects
STRESS granules, RNA-binding proteins, PROTEIN fractionation, CONDENSED matter, ATOMIC spectroscopy
Abstract

Biomolecules can be sequestered into membrane-less compartments, referred to as biomolecular condensates. Experimental and computational methods have helped define the physical-chemical properties of condensates. Less is known about how the high macromolecule concentrations in condensed phases contribute "solvent" interactions that can remodel the free-energy landscape of other condensate-resident proteins, altering thermally accessible conformations and, in turn, modulating function. Here, we use solution NMR spectroscopy to obtain atomic resolution insights into the interactions between the immature form of superoxide dismutase 1 (SOD1), which can mislocalize and aggregate in stress granules, and the RNA-binding protein CAPRIN1, a component of stress granules. NMR studies of CAPRIN1:SOD1 interactions, focused on both unfolded and folded SOD1 states in mixed phase and demixed CAPRIN1-based condensates, establish that CAPRIN1 shifts the SOD1 folding equilibrium toward the unfolded state through preferential interactions with the unfolded ensemble, with little change to the structure of the folded conformation. Key contacts between CAPRIN1 and the H80-H120 region of unfolded SOD1 are identified, as well as SOD1 interaction sites near both the arginine-rich and aromatic-rich regions of CAPRIN1. Unfolding of immature SOD1 in the CAPRIN1 condensed phase is shown to be coupled to aggregation, while a more stable zinc-bound, dimeric form of SOD1 is less susceptible to unfolding when solvated by CAPRIN1. Our work underscores the impact of the condensate solvent environment on the conformational states of resident proteins and supports the hypothesis that ALS mutations that decrease metal binding or dimerization function as drivers of aggregation in condensates. [ABSTRACT FROM AUTHOR]

Published
2024
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35. Stabilization of amyloidogenic immunoglobulin light chains by small molecules

Author

Morgan, Gareth J., Yan, Nicholas L., Mortenson, David E., Rennella, Enrico, Blundon, Joshua M., Gwin, Ryan M., Lin, Chung-Yon, Stanfield, Robyn L., Brown, Steven J., Rosen, Hugh, Spicer, Timothy P., Fernandez-Vega, Virneliz, Merlini, Giampaolo, Kay, Lewis E., Wilson, Ian A., and Kelly, Jeffery W.

Published
2019

40. Gadolinium-Based NMR Spin Relaxation Measurements of Near-Surface Electrostatic Potentials of Biomolecules

Author

Yu, Binhan, Bolik-Coulon, Nicolas, Rangadurai, Atul K., Kay, Lewis E., and Iwahara, Junji

Abstract

NMR spectroscopy is an important tool for the measurement of the electrostatic properties of biomolecules. To this point, paramagnetic relaxation enhancements (PREs) of 1H nuclei arising from nitroxide cosolutes in biomolecular solutions have been used to measure effective near-surface electrostatic potentials (ϕENS) of proteins and nucleic acids. Here, we present a gadolinium (Gd)-based NMR method, exploiting Gd chelates with different net charges, for measuring ϕENSvalues and demonstrate its utility through applications to a number of biomolecular systems. The use of Gd-based cosolutes offers several advantages over nitroxides for ϕENSmeasurements. First, unlike nitroxide compounds, Gd chelates enable electrostatic potential measurements on oxidation-sensitive proteins that require reducing agents. Second, the large electron spin quantum number of Gd (7/2) results in notably larger PREs for Gd chelates when used at the same concentrations as nitroxide radicals. Thus, it is possible to measure ϕENSvalues exclusively from + and – charged compounds even for highly charged biomolecules, avoiding the use of neutral cosolutes that, as we further establish here, limits the accuracy of the measured electrostatic potentials. In addition, the smaller concentrations of cosolutes required minimize potential binding to sites on macromolecules. Fourth, the closer proximity of the paramagnetic center and charged groups within Gd chelates, in comparison to the corresponding nitroxide compounds, enables more accurate predictions of ϕENSpotentials for cross-validation of the experimental results. The Gd-based method described here, thus, broadens the applicability of studies of biomolecular electrostatics using solution NMR spectroscopy.

Published
2024
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41. The Linker between the Dimerization and Catalytic Domains of the CheA Histidine Kinase Propagates Changes in Structure and Dynamics That Are Important for Enzymatic Activity

Author

Wang, Xiqing, Vallurupalli, Pramodh, Vu, Anh, Lee, Kwangwoon, Sun, Sheng, Bai, Wen-Ju, Wu, Chun, Zhou, Hongjun, Shea, Joan-Emma, Kay, Lewis E, and Dahlquist, Frederick W

Subjects
Biochemistry and Cell Biology, Chemical Sciences, Biological Sciences, Bacterial Proteins, Catalytic Domain, Enzyme Activation, Histidine Kinase, Models, Molecular, Phosphorylation, Protein Kinases, Protein Multimerization, Thermotoga maritima, Medicinal and Biomolecular Chemistry, Medical Biochemistry and Metabolomics, Biochemistry & Molecular Biology, Biochemistry and cell biology, Medical biochemistry and metabolomics, Medicinal and biomolecular chemistry
Abstract

The histidine kinase, CheA, couples environmental stimuli to changes in bacterial swimming behavior, converting a sensory signal to a chemical signal in the cytosol via autophosphorylation. The kinase activity is regulated in the platform of chemotaxis signaling complexes formed by CheW, chemoreceptors, and the regulatory domain of CheA. Our previous computational and mutational studies have revealed that two interdomain linkers play important roles in CheA's enzymatic activity. Of the two linkers, one that connects the dimerization and ATP binding domains is essential for both basal autophosphorylation and activation of the kinase. However, the mechanistic role of this linker remains unclear, given that it is far from the autophosphorylation reaction center (the ATP binding site). Here we investigate how this interdomain linker is coupled to CheA's enzymatic activity. Using modern nuclear magnetic resonance (NMR) techniques, we find that by interacting with the catalytic domain, the interdomain linker initiates long-range structural and dynamic changes directed toward the catalytic center of the autophosphorylation reaction. Subsequent biochemical assays define the functional relevance of these NMR-based observations. These findings extend our understanding of the chemotaxis signal transduction pathway.

Published
2014

48. A Magnetic Resonance Realization of Decoherence-Free Quantum Computation

Author

Ollerenshaw, Jason E., Lidar, Daniel A., and Kay, Lewis E.

Subjects
Quantum Physics
Abstract

We report the realization, using nuclear magnetic resonance techniques, of the first quantum computer that reliably executes an algorithm in the presence of strong decoherence. The computer is based on a quantum error avoidance code that protects against a class of multiple-qubit errors. The code stores two decoherence-free logical qubits in four noisy physical qubits. The computer successfully executes Grover's search algorithm in the presence of arbitrarily strong engineered decoherence. A control computer with no decoherence protection consistently fails under the same conditions., Comment: 5 pages with 3 figures, revtex4, accepted by Physical Review Letters; v2 minor revisions to content

Published
2003
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