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Structural Role of Glycine in Amyloid Fibrils Formed from Transmembrane α-Helices†
journal contribution
posted on 2005-03-08, 00:00 authored by Wei Liu, Evan Crocker, Wenyi Zhang, James I. Elliott, Burkhard Luy, Huilin Li, Saburo Aimoto, Steven O. SmithAmyloid 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-β-sheet structure
where main chain hydrogen bonding occurs between β-strands in the direction of the fibril axis. However,
the structural basis for how the membrane-spanning helix is converted into a β-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 β-sheets. We show that glycines in the glycophorin A transmembrane helix promote
extended β-strand formation when the helix partitions into aqueous environments and stabilize the packing
of β-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.