Functional diversification of the chemical landscapes of yeast Sec14-like phosphatidylinositol transfer protein lipid-binding cavities

• Published in: The Journal of biological chemistry Vol. 294; no. 50; pp. 19081 - 19098
• Main Authors: Tripathi, Ashutosh, Martinez, Elliott, Obaidullah, Ahmad J., Lete, Marta G., Lönnfors, Max, Khan, Danish, Soni, Krishnakant G., Mousley, Carl J., Kellogg, Glen E., Bankaitis, Vytas A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.12.2019; American Society for Biochemistry and Molecular Biology
• Subjects: Binding Sites; Carrier Proteins - chemistry; Carrier Proteins - metabolism; cavity mapping; computational biology; lipid metabolism; Lipids; Lipids - chemistry; Models, Molecular; phosphatidylinositol transfer proteins; phosphoinositide; Phospholipid Transfer Proteins - chemistry; Phospholipid Transfer Proteins - metabolism; Saccharomyces cerevisiae - chemistry; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins - chemistry; Saccharomyces cerevisiae Proteins - metabolism; Sec14-domain; signaling; squalene; sterol; computational biology; Sec14-domain; signaling; sterol; phosphatidylinositol transfer proteins; lipid metabolism; squalene; phosphoinositide; cavity mapping
• DOI: 10.1074/jbc.RA119.011153
• ISSN: 0021-9258; 1083-351X

Phosphatidylinositol-transfer proteins (PITPs) are key regulators of lipid signaling in eukaryotic cells. These proteins both potentiate the activities of phosphatidylinositol (PtdIns) 4-OH kinases and help channel production of specific pools of phosphatidylinositol 4-phosphate (PtdIns(4)P) dedicated to specific biological outcomes. In this manner, PITPs represent a major contributor to the mechanisms by which the biological outcomes of phosphoinositide are diversified. The two-ligand priming model proposes that the engine by which Sec14-like PITPs potentiate PtdIns kinase activities is a heterotypic lipid-exchange cycle where PtdIns is a common exchange substrate among the Sec14-like PITP family, but the second exchange ligand varies with the PITP. A major prediction of this model is that second-exchangeable ligand identity will vary from PITP to PITP. To address the heterogeneity in the second exchange ligand for Sec14-like PITPs, we used structural, computational, and biochemical approaches to probe the diversities of the lipid-binding cavity microenvironments of the yeast Sec14-like PITPs. The collective data report that yeast Sec14-like PITP lipid-binding pockets indeed define diverse chemical microenvironments that translate into differential ligand-binding specificities across this protein family.