Scaffolding Function of PI3Kgamma Emerges from Enzyme's Shadow. Issue 6 (24th March 2017)

• Record Type: Journal Article
• Authors: Mohan, Maradumane L; Naga Prasad, Sathyamangla V
• Is Part Of: Journal of molecular biology. Volume 429:Issue 6(2017)
• Page Start: 763
• Page End: 772
• Publication Date: 2017-03-24
• Subjects: PKA protein kinase A -- PI3K phosphoinositide 3-kinase -- PtdIns phosphatidylinositols -- RTK receptor tyrosine kinase -- GPCR G-protein-coupled receptor -- PIP3 PtdIns (3, 4, 5)-triphosphate -- PI3Kγ phosphoinositide 3-kinase γ -- βAR β-adrenergic receptor -- PI3Kγ-KD PI3Kγ knock-in -- EPC endothelial progenitor cell -- BBB blood–brain barrier -- MMP matrix metalloproteinase -- ADHD attention-deficit/hyperactivity disorder -- SNP single-nucleotide polymorphism -- PP2A protein phosphatase 2A -- PDE phosphodiesterase -- cAMP cyclic-adenosine monophosphate; phosphoinositide 3-kinase -- kinase-independent function -- scaffolding function -- signal transduction -- enzymes; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2017.01.023
• Languages: English
• ISSNs: 0022-2836

Abstract

Abstract: Traditionally, an enzyme is a protein that mediates biochemical action by binding to the substrate and by catalyzing the reaction that translates external cues into biological responses. Sequential dissemination of information from one enzyme to another facilitates signal transduction in biological systems providing for feed-forward and feed-back mechanisms. Given this viewpoint, an enzyme without its catalytic activity is generally considered to be an inert organizational protein without catalytic function and has classically been termed as pseudo-enzymes. However, pseudo-enzymes still have biological function albeit non-enzymatic like serving as a chaperone protein or an interactive platform between proteins. In this regard, majority of the studies have focused solely on the catalytic role of enzymes in biological function, overlooking the potentially critical non-enzymatic roles. Increasing evidence from recent studies implicate that the scaffolding function of enzymes could be as important in signal transduction as its catalytic activity, which is an antithesis to the definition of enzymes. Recognition of non-enzymatic functions could be critical, as these unappreciated roles may hold clues to the ineffectiveness of kinase inhibitors in pathology, which is characteristically associated with increased enzyme expression. Using an established enzyme phosphoinositide 3-kinase γ, we discuss the insights obtained from the scaffolding function and how this non-canonical role could contribute to/alter the outcomes in pathology like cancer and heart failure. Also, we hope that with this review, we provide a forum and a starting point to discuss the idea that catalytic function alone may not account for all the actions observed with increased expression of the enzyme. Graphical Abstract: Highlights: Enzymes harbor tertiary structures providing non-catalytic docking sites for proteins. Docked proteins are kinase-independently regulated by enzymes. Enzyme scaffolded proteins could be recruited to non-classical sites or sequestered. Kinase-independent function could synergize or antagonize with kinase activity. Kinase inhibitors may need reconsideration in view of kinase-independent function.