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  1. Article ; Online: Breakage of the oligomeric CaMKII hub by the regulatory segment of the kinase

    Deepti Karandur / Moitrayee Bhattacharyya / Zijie Xia / Young Kwang Lee / Serena Muratcioglu / Darren McAffee / Ethan D McSpadden / Baiyu Qiu / Jay T Groves / Evan R Williams / John Kuriyan

    eLife, Vol

    2020  Volume 9

    Abstract: Ca2+/calmodulin-dependent protein kinase II (CaMKII) is an oligomeric enzyme with crucial roles in neuronal signaling and cardiac function. Previously, we showed that activation of CaMKII triggers the exchange of subunits between holoenzymes, potentially ...

    Abstract Ca2+/calmodulin-dependent protein kinase II (CaMKII) is an oligomeric enzyme with crucial roles in neuronal signaling and cardiac function. Previously, we showed that activation of CaMKII triggers the exchange of subunits between holoenzymes, potentially increasing the spread of the active state (Stratton et al., 2014; Bhattacharyya et al., 2016). Using mass spectrometry, we show now that unphosphorylated and phosphorylated peptides derived from the CaMKII-α regulatory segment bind to the CaMKII-α hub and break it into smaller oligomers. Molecular dynamics simulations show that the regulatory segments dock spontaneously at the interface between hub subunits, trapping large fluctuations in hub structure. Single-molecule fluorescence intensity analysis of CaMKII-α expressed in mammalian cells shows that activation of CaMKII-α results in the destabilization of the holoenzyme. Our results suggest that release of the regulatory segment by activation and phosphorylation allows it to destabilize the hub, producing smaller assemblies that might reassemble to form new holoenzymes.
    Keywords CaMKII ; activation-dependent disassembly ; spread of activation state ; molecular dynamics simulation ; native mass spectrometry ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 612
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article: Simultaneous Measurements of Mass and Collisional Cross-Section of Single Ions with Charge Detection Mass Spectrometry

    Elliott, Andrew G / Anna C. Susa / Conner C. Harper / Evan R. Williams / Haw-Wei Lin / Zijie Xia

    Analytical chemistry. 2017 July 18, v. 89, no. 14

    2017  

    Abstract: The masses and mobilities of single multiply charged ions of cytochrome c, ubiquitin, myoglobin, and bovine serum albumin formed by electrospray ionization are measured using charge detection mass spectrometry (CDMS). Single ions are trapped and ... ...

    Abstract The masses and mobilities of single multiply charged ions of cytochrome c, ubiquitin, myoglobin, and bovine serum albumin formed by electrospray ionization are measured using charge detection mass spectrometry (CDMS). Single ions are trapped and repeatedly measured as they oscillate inside an electrostatic ion trap with cone electrodes for up to the maximum trapping time set at 500 ms. The histograms of the many single ion oscillation frequencies have resolved peaks that correspond to the different charge states of each protein. The m/z of each ion is determined from the initial oscillation frequency histogram, and the evolution of the ion energy with time is obtained from the changing frequency. A short-time Fourier transform of the time-domain data indicates that the increase in ion frequency occurs gradually with time with occasional sudden jumps in frequency. The frequency jumps are similar for each protein and may be caused by collision-induced changes in the ion trajectory. The rate of the gradual frequency shift increases with protein mass and charge state. This gradual frequency change is due to ion energy loss from collisions with the background gas. The total energy lost by an ion is determined from the latter frequency shifts normalized to a 500 ms lifetime, and these values increase nearly linearly with measured collisional cross-sections for these protein ions. These results show that the mass and collisional cross-section of single multiply charged ions can be obtained from these CDMS measurements by using proteins with known collisional cross-sections for calibration.
    Keywords bovine serum albumin ; cytochrome c ; electrodes ; energy ; ionization ; ions ; mass spectrometry ; myoglobin ; ubiquitin
    Language English
    Dates of publication 2017-0718
    Size p. 7701-7708.
    Publishing place American Chemical Society
    Document type Article
    ZDB-ID 1508-8
    ISSN 1520-6882 ; 0003-2700
    ISSN (online) 1520-6882
    ISSN 0003-2700
    DOI 10.1021/acs.analchem.7b01675
    Database NAL-Catalogue (AGRICOLA)

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  3. Article ; Online: Molecular mechanism of activation-triggered subunit exchange in Ca2+/calmodulin-dependent protein kinase II

    Moitrayee Bhattacharyya / Margaret M Stratton / Catherine C Going / Ethan D McSpadden / Yongjian Huang / Anna C Susa / Anna Elleman / Yumeng Melody Cao / Nishant Pappireddi / Pawel Burkhardt / Christine L Gee / Tiago Barros / Howard Schulman / Evan R Williams / John Kuriyan

    eLife, Vol

    2016  Volume 5

    Abstract: Activation triggers the exchange of subunits in Ca2+/calmodulin-dependent protein kinase II (CaMKII), an oligomeric enzyme that is critical for learning, memory, and cardiac function. The mechanism by which subunit exchange occurs remains elusive. We ... ...

    Abstract Activation triggers the exchange of subunits in Ca2+/calmodulin-dependent protein kinase II (CaMKII), an oligomeric enzyme that is critical for learning, memory, and cardiac function. The mechanism by which subunit exchange occurs remains elusive. We show that the human CaMKII holoenzyme exists in dodecameric and tetradecameric forms, and that the calmodulin (CaM)-binding element of CaMKII can bind to the hub of the holoenzyme and destabilize it to release dimers. The structures of CaMKII from two distantly diverged organisms suggest that the CaM-binding element of activated CaMKII acts as a wedge by docking at intersubunit interfaces in the hub. This converts the hub into a spiral form that can release or gain CaMKII dimers. Our data reveal a three-way competition for the CaM-binding element, whereby phosphorylation biases it towards the hub interface, away from the kinase domain and calmodulin, thus unlocking the ability of activated CaMKII holoenzymes to exchange dimers with unactivated ones.
    Keywords subunit exchange ; structural transition ; kinase activation ; Ca2+/CaM stimulus ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2016-03-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Anthrax toxin receptor drives protective antigen oligomerization and stabilizes the heptameric and octameric oligomer by a similar mechanism.

    Alexander F Kintzer / Harry J Sterling / Iok I Tang / Evan R Williams / Bryan A Krantz

    PLoS ONE, Vol 5, Iss 11, p e

    2010  Volume 13888

    Abstract: Background Anthrax toxin is comprised of protective antigen (PA), lethal factor (LF), and edema factor (EF). These proteins are individually nontoxic; however, when PA assembles with LF and EF, it produces lethal toxin and edema toxin, respectively. ... ...

    Abstract Background Anthrax toxin is comprised of protective antigen (PA), lethal factor (LF), and edema factor (EF). These proteins are individually nontoxic; however, when PA assembles with LF and EF, it produces lethal toxin and edema toxin, respectively. Assembly occurs either on cell surfaces or in plasma. In each milieu, PA assembles into a mixture of heptameric and octameric complexes that bind LF and EF. While octameric PA is the predominant form identified in plasma under physiological conditions (pH 7.4, 37°C), heptameric PA is more prevalent on cell surfaces. The difference between these two environments is that the anthrax toxin receptor (ANTXR) binds to PA on cell surfaces. It is known that the extracellular ANTXR domain serves to stabilize toxin complexes containing the PA heptamer by preventing premature PA channel formation--a process that inactivates the toxin. The role of ANTXR in PA oligomerization and in the stabilization of toxin complexes containing octameric PA are not understood. Methodology Using a fluorescence assembly assay, we show that the extracellular ANTXR domain drives PA oligomerization. Moreover, a dimeric ANTXR construct increases the extent of and accelerates the rate of PA assembly relative to a monomeric ANTXR construct. Mass spectrometry analysis shows that heptameric and octameric PA oligomers bind a full stoichiometric complement of ANTXR domains. Electron microscopy and circular dichroism studies reveal that the two different PA oligomers are equally stabilized by ANTXR interactions. Conclusions We propose that PA oligomerization is driven by dimeric ANTXR complexes on cell surfaces. Through their interaction with the ANTXR, toxin complexes containing heptameric and octameric PA oligomers are similarly stabilized. Considering both the relative instability of the PA heptamer and extracellular assembly pathway identified in plasma, we propose a means to regulate the development of toxin gradients around sites of infection during anthrax pathogenesis.
    Keywords Medicine ; R ; Science ; Q
    Subject code 540
    Language English
    Publishing date 2010-11-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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