title: Lipid headgroups modulate membrane insertion of pHLIP peptide.
abstract: The pH low insertion peptide (pHLIP) is an important tool for drug delivery and visualization of acidic tissues produced by various maladies, including cancer, inflammation, and ischemia. Numerous studies indicate that pHLIP exists in three states: unfolded and soluble in water at neutral pH (State I), unfolded and bound to the surface of a phosphatidylcholine membrane at neutral pH (State II), and inserted across the membrane as an α-helix at low pH (State III). Here we report how changes in lipid composition modulate this insertion scheme. First, the presence of either anionic lipids, cholesterol, or phosphoethanolamine eliminates membrane binding at neutral pH (State II). Second, the apparent pKa for the insertion transition (State I → State III) is increased with increasing content of anionic lipids, suggesting that electrostatic interactions in the interfacial region modulate protonation of acidic residues of pHLIP responsible for transbilayer insertion. These findings indicate a possibility for triggering protonation-coupled conformational switching in proteins at membrane interfaces through changes in lipid composition.
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kyrychenko
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Kansas Medical Center, Kansas City, Kansas.
authors.forename: Victor
authors.initials: V
authors.lastname: Vasquez-Montes
authors.affiliation: Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Martin B
authors.initials: MB
authors.lastname: Ulmschneider
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Kansas Medical Center, Kansas City, Kansas. Electronic address: aladokhin@kumc.edu.
authors.forename: Alexey S
authors.initials: AS
authors.lastname: Ladokhin
mesh_terms: D000595:Amino Acid Sequence; D002784:Cholesterol / Q000737:chemistry; D004983:Ethanolamines / Q000737:chemistry; D008051:Lipid Bilayers / Q000737:chemistry*; D008565:Membrane Proteins / Q000737:chemistry*; D008969:Molecular Sequence Data; D055672:Static Electricity
chemical_list: D004983:Ethanolamines; D008051:Lipid Bilayers; D008565:Membrane Proteins; C533201:pHLIP protein; C005448:phosphorylethanolamine; D002784:Cholesterol