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  1. Article ; Online: A proteome-wide map of chaperone-assisted protein refolding in a cytosol-like milieu.

    To, Philip / Xia, Yingzi / Lee, Sea On / Devlin, Taylor / Fleming, Karen G / Fried, Stephen D

    Proceedings of the National Academy of Sciences of the United States of America

    2022  Volume 119, Issue 48, Page(s) e2210536119

    Abstract: The journey by which proteins navigate their energy landscapes to their native structures is complex, involving (and sometimes requiring) many cellular factors and processes operating in partnership with a given polypeptide chain's intrinsic energy ... ...

    Abstract The journey by which proteins navigate their energy landscapes to their native structures is complex, involving (and sometimes requiring) many cellular factors and processes operating in partnership with a given polypeptide chain's intrinsic energy landscape. The cytosolic environment and its complement of chaperones play critical roles in granting many proteins safe passage to their native states; however, it is challenging to interrogate the folding process for large numbers of proteins in a complex background with most biophysical techniques. Hence, most chaperone-assisted protein refolding studies are conducted in defined buffers on single purified clients. Here, we develop a limited proteolysis-mass spectrometry approach paired with an isotope-labeling strategy to globally monitor the structures of refolding
    MeSH term(s) Cytosol/metabolism ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Escherichia coli Proteins/genetics ; Escherichia coli Proteins/metabolism ; Heat-Shock Proteins/metabolism ; Molecular Chaperones/genetics ; Molecular Chaperones/metabolism ; Protein Refolding ; Proteome/metabolism
    Chemical Substances Escherichia coli Proteins ; Heat-Shock Proteins ; Molecular Chaperones ; Proteome
    Language English
    Publishing date 2022-11-23
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2210536119
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 1148: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Synonymous Mutations Can Alter Protein Dimerization Through Localized Interface Misfolding Involving Self-entanglements.

    Lan, Pham Dang / Nissley, Daniel Allen / Sitarik, Ian / Vu, Quyen V / Jiang, Yang / To, Philip / Xia, Yingzi / Fried, Stephen D / Li, Mai Suan / O'Brien, Edward P

    Journal of molecular biology

    2024  Volume 436, Issue 6, Page(s) 168487

    Abstract: Synonymous mutations in messenger RNAs (mRNAs) can reduce protein-protein binding substantially without changing the protein's amino acid sequence. Here, we use coarse-grain simulations of protein synthesis, post-translational dynamics, and dimerization ... ...

    Abstract Synonymous mutations in messenger RNAs (mRNAs) can reduce protein-protein binding substantially without changing the protein's amino acid sequence. Here, we use coarse-grain simulations of protein synthesis, post-translational dynamics, and dimerization to understand how synonymous mutations can influence the dimerization of two E. coli homodimers, oligoribonuclease and ribonuclease T. We synthesize each protein from its wildtype, fastest- and slowest-translating synonymous mRNAs in silico and calculate the ensemble-averaged interaction energy between the resulting dimers. We find synonymous mutations alter oligoribonuclease's dimer properties. Relative to wildtype, the dimer interaction energy becomes 4% and 10% stronger, respectively, when translated from its fastest- and slowest-translating mRNAs. Ribonuclease T dimerization, however, is insensitive to synonymous mutations. The structural and kinetic origin of these changes are misfolded states containing non-covalent lasso-entanglements, many of which structurally perturb the dimer interface, and whose probability of occurrence depends on translation speed. These entangled states are kinetic traps that persist for long time scales. Entanglements cause altered dimerization energies for oligoribonuclease, as there is a large association (odds ratio: 52) between the co-occurrence of non-native self-entanglements and weak-binding dimer conformations. Simulated at all-atom resolution, these entangled structures persist for long timescales, indicating the conclusions are independent of model resolution. Finally, we show that regions of the protein we predict to have changes in entanglement are also structurally perturbed during refolding, as detected by limited-proteolysis mass spectrometry. Thus, non-native changes in entanglement at dimer interfaces is a mechanism through which oligomer structure and stability can be altered.
    MeSH term(s) Escherichia coli/enzymology ; Exoribonucleases/chemistry ; Exoribonucleases/genetics ; Kinetics ; Protein Folding ; Protein Multimerization/genetics ; Silent Mutation ; Cell Membrane/enzymology
    Chemical Substances exoribonuclease T (EC 3.1.13.-) ; Exoribonucleases (EC 3.1.-)
    Language English
    Publishing date 2024-02-09
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 80229-3
    ISSN 1089-8638 ; 0022-2836
    ISSN (online) 1089-8638
    ISSN 0022-2836
    DOI 10.1016/j.jmb.2024.168487
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 867: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Universal protein misfolding intermediates can bypass the proteostasis network and remain soluble and less functional.

    Nissley, Daniel A / Jiang, Yang / Trovato, Fabio / Sitarik, Ian / Narayan, Karthik B / To, Philip / Xia, Yingzi / Fried, Stephen D / O'Brien, Edward P

    Nature communications

    2022  Volume 13, Issue 1, Page(s) 3081

    Abstract: Some misfolded protein conformations can bypass proteostasis machinery and remain soluble in vivo. This is an unexpected observation, as cellular quality control mechanisms should remove misfolded proteins. Three questions, then, are: how do long-lived, ... ...

    Abstract Some misfolded protein conformations can bypass proteostasis machinery and remain soluble in vivo. This is an unexpected observation, as cellular quality control mechanisms should remove misfolded proteins. Three questions, then, are: how do long-lived, soluble, misfolded proteins bypass proteostasis? How widespread are such misfolded states? And how long do they persist? We address these questions using coarse-grain molecular dynamics simulations of the synthesis, termination, and post-translational dynamics of a representative set of cytosolic E. coli proteins. We predict that half of proteins exhibit misfolded subpopulations that bypass molecular chaperones, avoid aggregation, and will not be rapidly degraded, with some misfolded states persisting for months or longer. The surface properties of these misfolded states are native-like, suggesting they will remain soluble, while self-entanglements make them long-lived kinetic traps. In terms of function, we predict that one-third of proteins can misfold into soluble less-functional states. For the heavily entangled protein glycerol-3-phosphate dehydrogenase, limited-proteolysis mass spectrometry experiments interrogating misfolded conformations of the protein are consistent with the structural changes predicted by our simulations. These results therefore provide an explanation for how proteins can misfold into soluble conformations with reduced functionality that can bypass proteostasis, and indicate, unexpectedly, this may be a wide-spread phenomenon.
    MeSH term(s) Escherichia coli/genetics ; Escherichia coli/metabolism ; Escherichia coli Proteins/metabolism ; Molecular Chaperones/metabolism ; Protein Folding ; Proteolysis ; Proteostasis
    Chemical Substances Escherichia coli Proteins ; Molecular Chaperones
    Language English
    Publishing date 2022-06-02
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-022-30548-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: How synonymous mutations alter enzyme structure and function over long timescales.

    Jiang, Yang / Neti, Syam Sundar / Sitarik, Ian / Pradhan, Priya / To, Philip / Xia, Yingzi / Fried, Stephen D / Booker, Squire J / O'Brien, Edward P

    Nature chemistry

    2022  Volume 15, Issue 3, Page(s) 308–318

    Abstract: The specific activity of enzymes can be altered over long timescales in cells by synonymous mutations that alter a messenger RNA molecule's sequence but not the encoded protein's primary structure. How this happens at the molecular level is unknown. Here, ...

    Abstract The specific activity of enzymes can be altered over long timescales in cells by synonymous mutations that alter a messenger RNA molecule's sequence but not the encoded protein's primary structure. How this happens at the molecular level is unknown. Here, we use multiscale modelling of three Escherichia coli enzymes (type III chloramphenicol acetyltransferase, D-alanine-D-alanine ligase B and dihydrofolate reductase) to understand experimentally measured changes in specific activity due to synonymous mutations. The modelling involves coarse-grained simulations of protein synthesis and post-translational behaviour, all-atom simulations to test robustness and quantum mechanics/molecular mechanics calculations to characterize enzymatic function. We show that changes in codon translation rates induced by synonymous mutations cause shifts in co-translational and post-translational folding pathways that kinetically partition molecules into subpopulations that very slowly interconvert to the native, functional state. Structurally, these states resemble the native state, with localized misfolding near the active sites of the enzymes. These long-lived states exhibit reduced catalytic activity, as shown by their increased activation energies for the reactions they catalyse.
    MeSH term(s) Protein Biosynthesis ; Silent Mutation ; Codon/metabolism ; RNA, Messenger/genetics ; Ribosomes/metabolism ; Escherichia coli/genetics
    Chemical Substances Codon ; RNA, Messenger
    Language English
    Publishing date 2022-12-05
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2464596-5
    ISSN 1755-4349 ; 1755-4330
    ISSN (online) 1755-4349
    ISSN 1755-4330
    DOI 10.1038/s41557-022-01091-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Near-Infrared and Visible Photoactivation to Uncage Carbon Monoxide from an Aqueous-Soluble PhotoCORM.

    Jiang, Qin / Xia, Yingzi / Barrett, Jacob / Mikhailovsky, Alexander / Wu, Guang / Wang, Daqi / Shi, Pengfei / Ford, Peter C

    Inorganic chemistry

    2019  Volume 58, Issue 16, Page(s) 11066–11075

    Abstract: Multiphoton excitation allows one to access high energy excited states and perform valuable tasks in biological systems using tissue penetrating near-infrared (NIR) light. Here, we describe new photoactive manganese tricarbonyl complexes incorporating ... ...

    Abstract Multiphoton excitation allows one to access high energy excited states and perform valuable tasks in biological systems using tissue penetrating near-infrared (NIR) light. Here, we describe new photoactive manganese tricarbonyl complexes incorporating the ligand 4'-p-N,N-bis(2-hydroxyethyl)amino-benzyl-2,2':6',2″-terpyridine (TPYOH), which can serve as an antenna for two photon NIR excitation. Solutions of Mn(CO)
    Language English
    Publishing date 2019-08-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1484438-2
    ISSN 1520-510X ; 0020-1669
    ISSN (online) 1520-510X
    ISSN 0020-1669
    DOI 10.1021/acs.inorgchem.9b01581
    Database MEDical Literature Analysis and Retrieval System OnLINE

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