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    The Need for Speed: Run-On Oligomer Filament Formation Provides Maximum Speed with Maximum Sequestration of Activity

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    Barahona_et_al_final_withSI_pd ...
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    Final Accepted Manuscript
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    Author
    Barahona, Claudia J
    Basantes, L Emilia
    Tompkins, Kassidy J
    Heitman, Desirae M
    Chukwu, Barbara I
    Sanchez, Juan
    Sanchez, Jonathan L
    Ghadirian, Niloofar
    Park, Chad K
    Horton, N C
    Affiliation
    Univ Arizona, Dept Mol & Cellular Biol
    Issue Date
    2019-03-01
    Keywords
    antiphage mechanism
    enzyme kinetics
    enzyme mechanism
    filament forming enzymes
    kinetic simulations
    phage infection
    protein structure-function
    restriction endonuclease
    
    Metadata
    Show full item record
    Publisher
    AMER SOC MICROBIOLOGY
    Citation
    Barahona, C. J., Basantes, L. E., Tompkins, K. J., Heitman, D. M., Chukwu, B. I., Sanchez, J., ... & Horton, N. C. (2019). The Need for Speed: Run-On Oligomer Filament Formation Provides Maximum Speed with Maximum Sequestration of Activity. Journal of virology, 93(5), e01647-18.
    Journal
    JOURNAL OF VIROLOGY
    Rights
    Copyright © 2019 American Society for Microbiology. All Rights Reserved.
    Collection Information
    This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.
    Abstract
    Here, we investigate an unusual antiviral mechanism developed in the bacterium Streptomyces griseus. SgrAI is a type II restriction endonuclease that forms run-on oligomer filaments when activated and possesses both accelerated DNA cleavage activity and expanded DNA sequence specificity. Mutations disrupting the run-on oligomer filament eliminate the robust antiphage activity of wild-type SgrAI, and the observation that even relatively modest disruptions completely abolish this anti-viral activity shows that the greater speed imparted by the run-on oligomer filament mechanism is critical to its biological function. Simulations of DNA cleavage by SgrAI uncover the origins of the kinetic advantage of this newly described mechanism of enzyme regulation over more conventional mechanisms, as well as the origin of the sequestering effect responsible for the protection of the host genome against damaging DNA cleavage activity of activated SgrAI. IMPORTANCE This work is motivated by an interest in understanding the characteristics and advantages of a relatively newly discovered enzyme mechanism involving filament formation. SgrAI is an enzyme responsible for protecting against viral infections in its host bacterium and was one of the first such enzymes shown to utilize such a mechanism. In this work, filament formation by SgrAI is disrupted, and the effects on the speed of the purified enzyme as well as its function in cells are measured. It was found that even small disruptions, which weaken but do not destroy filament formation, eliminate the ability of SgrAI to protect cells from viral infection, its normal biological function. Simulations of enzyme activity were also performed and show how filament formation can greatly speed up an enzyme's activation compared to that of other known mechanisms, as well as to better localize its action to molecules of interest, such as invading phage DNA.
    Note
    6 month embargo; published online: 19 February 2019
    ISSN
    1098-5514
    PubMed ID
    30518649
    DOI
    10.1128/JVI.01647-18
    Version
    Final accepted manuscript
    Sponsors
    National Science Foundation [MCB-1410355]; Office of the Director, National Institutes of Health [S10OD013237]; National Institute of General Medical Sciences of the National Institutes of Health [T32GM008659]
    Additional Links
    https://jvi.asm.org/content/93/5/e01647-18
    ae974a485f413a2113503eed53cd6c53
    10.1128/JVI.01647-18
    Scopus Count
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    UA Faculty Publications

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