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Conformation and aggregation of selectively pegylated and lipidated gastric peptide hormone human PYY 3-36

DOI: 10.1021/acs.biomac.8b01209 DOI Help

Authors: Valeria Castelletto (University of Reading) , Ian W. Hamley (University of Reading) , Jani Seitsonen (Aalto University) , Janne Ruokolainen (Aalto University) , Gemma Harris (Diamond Light Source) , Kathrin Bellmann-sickert (Leipzig University) , Annette G. Beck-sickinger (Leipzig University)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biomacromolecules

State: Published (Approved)
Published: September 2018
Diamond Proposal Number(s): 14684 , 17118

Abstract: The gastric peptide hormone human PYY3-36 is a target for the development of therapeutics, especially for treatment of obesity. The conformation and aggregation behaviour of PEGylated and lipidated derivatives of this peptide is examined using a combination of fluorescence dye assays, circular dichroism (CD) spectroscopy, analytical ultracentrifugation (AUC) measurements, small-angle x-ray scattering (SAXS) and cryogenic-transmission electron microscopy (cryo-TEM). The behaviour of two PYY3-36 derivatives lipidated (with octyl chains) in different positions is compared to that of two derivatives with PEG attached at different residues and to that of the native peptide. We find that, unexpectedly, PYY3-36 forms amyloid fibril structures above a critical aggregation concentration. Formation of these structures is suppressed by PEGylation or lipidation. PEGylation significantly reduces the (reversible) loss of α-helix content observed on heating PYY3-36. The PEG conjugates form mainly monomeric structures in solution, coiled coil formation and other aggregation presumably being sterically hindered by swollen PEG chains. However, some small aggregates are detected by AUC. In complete contrast, both of the two lipidated peptides show the formation of spherical micelle-like structures which are small oligomeric aggregates. Our findings show that PEGylation and lipidation are complementary strategies to tune the conformation and aggregation of the important gastric peptide hormone human PYY3-36.

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: B21-High Throughput SAXS

Other Facilities: ESRF

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