title: A molecular switch in amyloid assembly: Met35 and amyloid beta-protein oligomerization.
abstract: Aberrant protein oligomerization is an important pathogenetic process in vivo. In Alzheimer's disease (AD), the amyloid beta-protein (Abeta) forms neurotoxic oligomers. The predominant in vivo Abeta alloforms, Abeta40 and Abeta42, have distinct oligomerization pathways. Abeta42 monomers oligomerize into pentamer/hexamer units (paranuclei) which self-associate to form larger oligomers. Abeta40 does not form these paranuclei, a fact which may explain the particularly strong linkage of Abeta42 with AD. Here, we sought to determine the structural elements controlling paranucleus formation as a first step toward the development of strategies for treating AD. Because oxidation of Met(35) is associated with altered Abeta assembly, we examined the role of Met(35) in controlling Abeta oligomerization. Oxidation of Met(35) in Abeta42 blocked paranucleus formation and produced oligomers indistinguishable in size and morphology from those produced by Abeta40. Systematic structural alterations of the C(gamma)(35)-substituent group revealed that its electronic nature, rather than its size (van der Waals volume), was the factor controlling oligomerization pathway choice. Preventing assembly of toxic Abeta42 paranuclei through selective oxidation of Met(35) thus represents a potential therapeutic approach for AD.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Gal
authors.initials: G
authors.lastname: Bitan
authors.forename: Bogdan
authors.initials: B
authors.lastname: Tarus
authors.forename: Sabrina S
authors.initials: SS
authors.lastname: Vollers
authors.forename: Hilal A
authors.initials: HA
authors.lastname: Lashuel
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Condron
authors.forename: John E
authors.initials: JE
authors.lastname: Straub
authors.forename: David B
authors.initials: DB
authors.lastname: Teplow
mesh_terms: D000682:Amyloid / Q000096:biosynthesis* / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D008715:Methionine / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D008715:Methionine