• Login
    View Item 
    •   Home
    • The Christie Research Publications Repository
    • All Christie Publications
    • View Item
    •   Home
    • The Christie Research Publications Repository
    • All Christie Publications
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of ChristieCommunitiesTitleAuthorsIssue DateSubmit DateSubjectsThis CollectionTitleAuthorsIssue DateSubmit DateSubjectsProfilesView

    My Account

    LoginRegister

    Local Links

    The Christie WebsiteChristie Library and Knowledge Service

    Statistics

    Display statistics

    Protein kinase Cα gain-of-function variant in Alzheimer's disease displays enhanced catalysis by a mechanism that evades down-regulation.

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    560467.pdf
    Size:
    1.391Mb
    Format:
    PDF
    Description:
    From UNPAYWALL
    Download
    Authors
    Callender, J
    Yang, Y
    Lordén, G
    Stephenson, Natalie L
    Jones, A
    Brognard, John
    Newton, A
    Affiliation
    Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093
    Issue Date
    2018-06-12
    
    Metadata
    Show full item record
    Abstract
    Conventional protein kinase C (PKC) family members are reversibly activated by binding to the second messengers Ca2+ and diacylglycerol, events that break autoinhibitory constraints to allow the enzyme to adopt an active, but degradation-sensitive, conformation. Perturbing these autoinhibitory constraints, resulting in protein destabilization, is one of many mechanisms by which PKC function is lost in cancer. Here, we address how a gain-of-function germline mutation in PKCα in Alzheimer's disease (AD) enhances signaling without increasing vulnerability to down-regulation. Biochemical analyses of purified protein demonstrate that this mutation results in an ∼30% increase in the catalytic rate of the activated enzyme, with no changes in the concentrations of Ca2+ or lipid required for half-maximal activation. Molecular dynamics simulations reveal that this mutation has both localized and allosteric effects, most notably decreasing the dynamics of the C-helix, a key determinant in the catalytic turnover of kinases. Consistent with this mutation not altering autoinhibitory constraints, live-cell imaging studies reveal that the basal signaling output of PKCα-M489V is unchanged. However, the mutant enzyme in cells displays increased sensitivity to an inhibitor that is ineffective toward scaffolded PKC, suggesting the altered dynamics of the kinase domain may influence protein interactions. Finally, we show that phosphorylation of a key PKC substrate, myristoylated alanine-rich C-kinase substrate, is increased in brains of CRISPR-Cas9 genome-edited mice containing the PKCα-M489V mutation. Our results unveil how an AD-associated mutation in PKCα permits enhanced agonist-dependent signaling via a mechanism that evades the cell's homeostatic down-regulation of constitutively active PKCα.
    Citation
    Protein kinase Cα gain-of-function variant in Alzheimer's disease displays enhanced catalysis by a mechanism that evades down-regulation. 2018, 115(24): E5497-E5505 Proc Natl Acad Sci U S A
    Journal
    Proceedings of the National Academy of Sciences of the United States of America
    URI
    http://hdl.handle.net/10541/621114
    DOI
    10.1073/pnas.1805046115
    PubMed ID
    29844158
    Type
    Article
    Language
    en
    ISSN
    1091-6490
    ae974a485f413a2113503eed53cd6c53
    10.1073/pnas.1805046115
    Scopus Count
    Collections
    All Christie Publications

    entitlement

    Related articles

    • Gain-of-function mutations in protein kinase Cα (PKCα) may promote synaptic defects in Alzheimer's disease.
    • Authors: Alfonso SI, Callender JA, Hooli B, Antal CE, Mullin K, Sherman MA, Lesné SE, Leitges M, Newton AC, Tanzi RE, Malinow R
    • Issue date: 2016 May 10
    • Enhanced activity of Alzheimer disease-associated variant of protein kinase Cα drives cognitive decline in a mouse model.
    • Authors: Lordén G, Wozniak JM, Doré K, Dozier LE, Cates-Gatto C, Patrick GN, Gonzalez DJ, Roberts AJ, Tanzi RE, Newton AC
    • Issue date: 2022 Nov 23
    • Electrostatic and hydrophobic interactions differentially tune membrane binding kinetics of the C2 domain of protein kinase Cα.
    • Authors: Scott AM, Antal CE, Newton AC
    • Issue date: 2013 Jun 7
    • Protein Kinase Cα (PKCα) Is Resistant to Long Term Desensitization/Down-regulation by Prolonged Diacylglycerol Stimulation.
    • Authors: Lum MA, Barger CJ, Hsu AH, Leontieva OV, Black AR, Black JD
    • Issue date: 2016 Mar 18
    • Presenilin dependence of phospholipase C and protein kinase C signaling.
    • Authors: Dehvari N, Cedazo-Minguez A, Isacsson O, Nilsson T, Winblad B, Karlström H, Benedikz E, Cowburn RF
    • Issue date: 2007 Aug
    DSpace software (copyright © 2002 - 2025)  DuraSpace
    Quick Guide | Contact Us
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.