Abstract
Yeast Sfh5 is an unusual member of the Sec14-like phosphatidylinositol transfer protein (PITP) family. Whereas PITPs are defined by their abilities to transfer phosphatidylinositol between membranes in vitro, and to stimulate phosphoinositide signaling in vivo, Sfh5 does not exhibit these activities. Rather, Sfh5 is a redox-active penta-coordinate high spin FeIII hemoprotein with an unusual heme-binding arrangement that involves a co-axial tyrosine/histidine coordination strategy and a complex electronic structure connecting the open shell iron d-orbitals with three aromatic ring systems. That Sfh5 is not a PITP is supported by demonstrations that heme is not a readily exchangeable ligand, and that phosphatidylinositol-exchange activity is resuscitated in heme binding-deficient Sfh5 mutants. The collective data identify Sfh5 as the prototype of a new class of fungal hemoproteins, and emphasize the versatility of the Sec14-fold as scaffold for translating the binding of chemically distinct ligands to the control of diverse sets of cellular activities.
Highlights
Lipid metabolism is a major component of the eukaryotic strategy for organizing and regulating cell signaling
Of the six Sec14-like phosphatidylinositol transfer protein (PITP) expressed in yeast, Sfh5 exhibits several distinguishing properties
The electrostatic properties of Sfh5 are unique among the cohort of yeast Sec14-like PITPs as both the protein surface and large regions of the putative lipid-binding cavity exhibit significant electropositive character (Tripathi et al, 2019)
Summary
Lipid metabolism is a major component of the eukaryotic strategy for organizing and regulating cell signaling. The PtdIns 4-OH kinases are biologically insufficient enzymes that are unable to generate sufficient PtdIns4P to override the action of erasers of PtdIns4P signaling, such as lipid phosphatases and PtdIns4P-sequestering activities, to support productive signaling These deficiencies are overcome by the action of Sec14-like PtdIns transfer proteins (PITPs) that stimulate PtdIns 4-OH kinase activities so that sufficient PtdIns4P pools are generated in a precisely regulated manner (Ile et al, 2006). Structure-based predictions that PtdIns-binding is conserved across the Sec superfamily, while the nature of the priming lipid is diversified, suggests a mechanism where the PITP acts as a metabolic sensor for activating PtdIns4P signaling in response to a metabolic input (Schaaf et al, 2008; Bankaitis et al, 2010; Grabon et al, 2019). Sfh is the founding member of a new and conserved class of fungal hemoproteins, and provides the first demonstration that the spectrum of ligands for PITP-like proteins extends beyond lipids
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