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Defining how viruses manipulate lipid phosphoinositides through activation of PI4P kinases to mediate viral replication
Author(s) -
Burke John E.,
McPhail Jacob A.,
Rathinaswamy Manoj,
Jenkins Meredith L.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.02060
Subject(s) - kinase , biology , gtpase , microbiology and biotechnology , computational biology , rab , nuclear transport , structural biology , cell nucleus , nucleus
Phosphoinositide kinases are central regulators of myriad cellular processes, and their misregulation is causative of multiple human diseases. We are currently focusing on the structural basis for the regulation of phosphoinositide kinases, specifically the Golgi localised phosphatidylinositol 4‐kinase beta (PI4KB). We have identified a previously uncharacterised protein binding partner of PI4KB, the GTPase regulatory protein c10orf76 1, and revealed novel insight into an unexpected PI4K positive feedback loop. Using a combined hydrogen deuterium exchange mass spectrometry (HDX‐MS) and structural biology approach we have defined the molecular basis of regulation by the protein c10orf76, revealing novel insight into the role of these PI4KB in viral replication. This has revealed key insight into unexpected feedback loops with Ras superfamily GTPases. Overall, this approach has provided a novel toolbox of engineered mutations to tease out the molecular basis of regulation of phosphoinositide kinases in both homeostasis and disease, and has revealed novel opportunities for the development of small molecule therapeutics for multiple pathogenic viral infections. Support or Funding Information Research was supported by the Canadian Institute of Health Research (CRN‐142393), and salary award for the CIHR new investigator and MSFHR scholar programs.1 McPhail et al EMBO Reports 2018 . In press