Roles of Intrinsically Disordered Regions in Phosphoinositide 3-kinase Biocatalysis
Document Type
Book Chapter
Publication Date
2023
Keywords
PI3 Kinase, Intrinsically Disordered Region, Aberrant Protein Function, Protein–protein Interaction, Signaling Pathway, Regulation
Digital Object Identifier (DOI)
https://doi.org/10.1016/B978-0-323-99533-7.00001-7
Abstract
Amongst a host of intracellular signaling pathways that maintain cellular homeostasis, the PI3K/PTEN/AKT/mTOR (phosphoinositide 3-kinase/phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase/Ak strain transforming kinase/mammalian target of rapamycin) pathway plays a central role in transducing signals via a myriad of receptors, each with distinct function. When a ligand binds and activates a membrane receptor, members of the PI3K enzyme family associate with the receptor and get activated. PI3K then initiates downstream signaling by activating multiple kinases that integrate signals regulating cellular growth, differentiation, cell motility, cytoskeletal remodeling, trafficking of intracellular organelles, cell shape, movement, and survival. In addition, levels of intracellular amino acids, energy needs, oxygen, and various other types of biochemical and biomechanical stressors also modulated PI3K pathway. Therefore PI3K pathway plays integral role in cellular physiology and homeostasis.
However, activating PI3K mutations hyperactivate downstream PI3K pathway, leading to abnormal cell physiology and pathologies, including cardiovascular and neurological diseases, organ fibrosis, and multiple organ malignancies. While inhibition of PI3K by active site targeting is employed in the clinic, there remains challenges associated with on-target and off-target toxicities. Consequently, treatment delays, dose alterations, and/or change in inhibitors, treatment interruption or complete treatment discontinuation are not uncommon in the clinic. Keeping these challenges in mind, in this chapter, we attempt to thoroughly understand biochemistry and molecular biology of nonkinase domains and regulatory subunits of PI3Ks to provide molecular evidence that may aid in developing alternative PI3K inhibitors. Our main goal is to define intrinsically disordered regions (IDRs) involved in PI3K activation with an aim to leveraging this knowledge in inhibiting aberrant PI3K activity driving diseases. We have analyzed regulatory subunits and domains of PI3K proteins and identified IDRs that may contribute to PI3K function. While there are two major classes of PI3K enzymes, one activated by G-coupled protein receptors and the other activated by receptor tyrosine kinases, class IA PI3Ks are regulated by both mechanisms. In addition, the p85-family of regulatory subunits of class IA PI3Ks is a major influence on PI3K catalytic function. Therefore we focus on IDR in p85-family subunits that may contribute to enzyme function. It is anticipated that the detailed understanding of the mechanisms underlying modulation of PI3K enzyme function utilizing IDRs will further shed light on the normal cellular functions and may help in designing novel PI3K inhibitors for clinical treatment.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Roles of Intrinsically Disordered Regions in Phosphoinositide 3-kinase Biocatalysis, in M. N. Gupta & V. N. Uversky (Eds.), Structure and Intrinsic Disorder in Enzymology, Academic Press, p. 225-240
Scholar Commons Citation
Davé, Vrushank and Uversky, Vladimir N., "Roles of Intrinsically Disordered Regions in Phosphoinositide 3-kinase Biocatalysis" (2023). Molecular Medicine Faculty Publications. 1120.
https://digitalcommons.usf.edu/mme_facpub/1120
