title: HDL mimetic peptide ATI-5261 forms an oligomeric assembly in solution that dissociates to monomers upon dilution.
abstract: ATI-5261 is a 26-mer peptide that stimulates cellular cholesterol efflux with high potency. This peptide displays high aqueous solubility, despite having amphipathic α-helix structure and a broad nonpolar surface. These features suggested to us that ATI-5261 may adopt a specific form in solution, having favorable structural characteristics and dynamics. To test this, we subjected ATI-5261 to a series of biophysical studies and correlated self-association with secondary structure and activity. Gel-filtration chromatography and native gel electrophoresis indicated ATI-5261 adopted a discrete self-associated form of low molecular weight at concentrations >1 mg/mL. Formation of a discrete molecular species was verified by small-angle X-ray scattering (SAXS), which further revealed the peptide formed a tetrameric assembly having an elongated shape and hollow central core. This assembly dissociated to individual peptide strands upon dilution to concentrations required for promoting high-affinity cholesterol efflux from cells. Moreover, the α-helical content of ATI-5261 was exceptionally high (74.1 ± 6.8%) regardless of physical form and concentration. Collectively, these results indicate ATI-5261 displays oligomeric behavior generally similar to native apolipoproteins and dissociates to monomers of high α-helical content upon dilution. Optimizing self-association behavior and secondary structure may prove useful for improving the translatability and efficacy of apolipoprotein mimetic peptides.
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Donner Laboratory, University of California, Berkeley, Berkeley, California 94720, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.forename: Arti B
authors.initials: AB
authors.lastname: Patel
authors.forename: Vasanthy
authors.initials: V
authors.lastname: Narayanaswami
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Hura
authors.forename: Bo
authors.initials: B
authors.lastname: Hang
authors.forename: John K
authors.initials: JK
authors.lastname: Bielicki
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D051379:Mice; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D053838:Scattering, Small Angle; D012996:Solutions; D014961:X-Ray Diffraction
chemical_list: D016632:Apolipoprotein A-I; D010455:Peptides; D012996:Solutions