title: Stability and membrane orientation of the fukutin transmembrane domain: a combined multiscale molecular dynamics and circular dichroism study.
abstract: The N-terminal domain of fukutin-I has been implicated in the localization of the protein in the endoplasmic reticulum and Golgi Apparatus. It has been proposed to mediate this through its interaction with the thinner lipid bilayers found in these compartments. Here we have employed multiscale molecular dynamics simulations and circular dichroism spectroscopy to explore the structure, stability, and orientation of the short 36-residue N-terminus of fukutin-I (FK1TMD) in lipids with differing tail lengths. Our results show that FK1TMD adopts a stable helical conformation in phosphatidylcholine lipids when oriented with its principal axis perpendicular to the bilayer plane. The stability of the helix is largely insensitive to the lipid tail length, preventing hydrophobic mismatch by virtue of its mobility and ability to tilt within the lipid bilayers. This suggests that changes in FK1TMD tilt in response to bilayer properties may be implicated in the regulation of its trafficking. Coarse-grained simulations of the complex Golgi membrane suggest the N-terminal domain may induce the formation of microdomains in the surrounding membrane through its preferential interaction with 1,2-dipalmitoyl-sn-glycero-3-phosphatidylinositol 4,5-bisphosphate lipids.
authors.affiliation: School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Holdbrook
authors.forename: Yuk Ming
authors.initials: YM
authors.lastname: Leung
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Piggot
authors.forename: Phedra
authors.initials: P
authors.lastname: Marius
authors.forename: Philip T F
authors.initials: PT
authors.lastname: Williamson
authors.forename: Syma
authors.initials: S
authors.lastname: Khalid
mesh_terms: D000595:Amino Acid Sequence; D002942:Circular Dichroism; D008051:Lipid Bilayers / Q000737:chemistry*; D008565:Membrane Proteins / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010713:Phosphatidylcholines / Q000737:chemistry; D055550:Protein Stability; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D008051:Lipid Bilayers; D008565:Membrane Proteins; D010713:Phosphatidylcholines