title: Structural role of glycine in amyloid fibrils formed from transmembrane alpha-helices.
abstract: Amyloid fibrils associated with diseases such as Alzheimer's are often derived from the transmembrane helices of membrane proteins. It is known that the fibrils have a cross-beta-sheet structure where main chain hydrogen bonding occurs between beta-strands in the direction of the fibril axis. However, the structural basis for how the membrane-spanning helix is converted into a beta-sheet or how protofibrils associate into fibrils is not known. Here, we use a model peptide corresponding to a portion of the single transmembrane helix of glycophorin A to investigate the structural role of glycine in amyloid-like fibrils formed from transmembrane helices. Glycophorin A contains a GxxxG motif that is found in many transmembrane sequences including that of the amyloid precursor protein and prion protein. We propose that glycine, which mediates helix interactions in membrane proteins, also provides key packing motifs when it occurs in beta-sheets. We show that glycines in the glycophorin A transmembrane helix promote extended beta-strand formation when the helix partitions into aqueous environments and stabilize the packing of beta-sheets in the formation of amyloid-like fibrils. We demonstrate that fibrillization can be disrupted with a new class of inhibitors that target the molecular grooves created by glycine.
authors.affiliation: Department of Biochemistry and Cell Biology, Center for Structural Biology, Stony Brook University, Stony Brook, New York 11794-5215, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Evan
authors.initials: E
authors.lastname: Crocker
authors.forename: Wenyi
authors.initials: W
authors.lastname: Zhang
authors.forename: James I
authors.initials: JI
authors.lastname: Elliott
authors.forename: Burkhard
authors.initials: B
authors.lastname: Luy
authors.forename: Huilin
authors.initials: H
authors.lastname: Li
authors.forename: Saburo
authors.initials: S
authors.lastname: Aimoto
authors.forename: Steven O
authors.initials: SO
authors.lastname: Smith
mesh_terms: D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000648:ultrastructure; D015195:Drug Design; D005998:Glycine / Q000737:chemistry* / Q000378:metabolism*; D006021:Glycophorins / Q000138:chemical synthesis / Q000378:metabolism / Q000648:ultrastructure; D008565:Membrane Proteins / Q000138:chemical synthesis / Q000378:metabolism* / Q000648:ultrastructure; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism; D017433:Protein Structure, Secondary
chemical_list: D016564:Amyloid beta-Protein Precursor; D006021:Glycophorins; D008565:Membrane Proteins; D010446:Peptide Fragments; D005998:Glycine