title: Model peptides uncover the role of the β-secretase transmembrane sequence in metal ion mediated oligomerization.
abstract: The β-secretase or β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the enzyme responsible for the formation of amyloid-β peptides, which have a major role in Alzheimer pathogenesis. BACE1 has a transmembrane sequence (TMS), which makes it unique among related proteases. We noticed that the BACE1 TMS contains an uncommon sulfur-rich motif. The sequence MxxxCxxxMxxxCxMxC spans the entire TMS, resembles metal ion binding motifs, and is highly conserved among homologues. We used a synthetic 31-mer model peptide comprising the TMS to study metal ion binding and oligomerization. Applying diverse biochemical and biophysical techniques, we detected dimer and trimer formation of the TMS peptide with copper ions. Replacement of the central Cys466 by Ala essentially abolished these effects. We show that the peptide undergoes a redox reaction with copper ions resulting in a disulfide bridge involving Cys466. Further, we find peptide trimerization that depends on the presence of monovalent copper ions and the sulfhydryl group of Cys466. We identified Cys466 as a key residue for metal ion chelation and to be the core of an oligomerization motif of the BACE1-TMS peptide. Our results demonstrate a novel metal ion controlled oligomerization of the BACE1 TMS, which could have an enormous therapeutic importance against Alzheimer disease.
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University , 3655 Promenade Sir William Osler, H3G 1Y6 Montreal, Canada.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Munter
authors.forename: Holger
authors.initials: H
authors.lastname: Sieg
authors.forename: Tobias
authors.initials: T
authors.lastname: Bethge
authors.forename: Filip
authors.initials: F
authors.lastname: Liebsch
authors.forename: Frank S
authors.initials: FS
authors.lastname: Bierkandt
authors.forename: Michael
authors.initials: M
authors.lastname: Schleeger
authors.forename: Heiko J
authors.initials: HJ
authors.lastname: Bittner
authors.forename: Joachim
authors.initials: J
authors.lastname: Heberle
authors.forename: Norbert
authors.initials: N
authors.lastname: Jakubowski
authors.forename: Peter W
authors.initials: PW
authors.lastname: Hildebrand
authors.forename: Gerd
authors.initials: G
authors.lastname: Multhaup
mesh_terms: D020816:Amino Acid Motifs; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry*; D000818:Animals; D002942:Circular Dichroism; D003124:Colorimetry; D003300:Copper / Q000032:analysis*; D006801:Humans; D051379:Mice; D008954:Models, Biological; D051381:Rats; D016415:Sequence Alignment; D017550:Spectroscopy, Fourier Transform Infrared; D013455:Sulfur / Q000737:chemistry*
chemical_list: D013455:Sulfur; D003300:Copper; D053829:Amyloid Precursor Protein Secretases