title: Stereoisomers Probe Steric Zippers in Amyloid-β.
abstract: Shape complementarity between close-packed residues plays a critical role in the amyloid aggregation process. Here, we probe such "steric zipper" interactions in amyloid-β (Aβ40), whose aggregation is linked to Alzheimer's disease, by replacing natural residues by their stereoisomers. Such mutations are expected to specifically destabilize the shape sensitive "packing" interactions, which may potentially increase their solubility and change other properties. We study the stereomutants DF19 and DL34 and also the DA2/DF4/DH6/DS8 mutant of Aβ40. F19-L34 is a critical contact in a tightly packed region of Aβ, while residues 1-9 are known to be disordered. While both DF19 and DL34 slow down the kinetics of aggregation and form amyloid fibrils efficiently, only DL34 increases the final solubility. DF19 gives rise to additional off-pathway aggregation which results in large, kinetically stable aggregates, and has lower net solubility. DA2/DF4/DH6/DS8 does not have an effect on the kinetics or the solubility. Notably, both DF19 and DL34 oligomers have a significantly lower level of interactions with lipid vesicles and live cells. We conclude that stereoisomers can cause complex site dependent changes in amyloid properties, and provide an effective tool to determine the role of individual residues in shaping the packed interiors of amyloid aggregates.
authors.affiliation: Department of Chemical Science, Tata Institute of Fundamental Research , Homi Bhabha Road, Colaba, Mumbai 400005, India.
authors.forename: Bappaditya
authors.initials: B
authors.lastname: Chandra
authors.affiliation: Institut für Medizinische Physik und Biophysik, Universität Leipzig , Härtelstrasse 16-18, D-04107 Leipzig, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Korn
authors.affiliation: Department of Chemical Science, Tata Institute of Fundamental Research , Homi Bhabha Road, Colaba, Mumbai 400005, India.
authors.forename: Barun Kumar
authors.initials: BK
authors.lastname: Maity
authors.affiliation: Institut für Medizinische Physik und Biophysik, Universität Leipzig , Härtelstrasse 16-18, D-04107 Leipzig, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Adler
authors.affiliation: Department of Chemical Science, Tata Institute of Fundamental Research , Homi Bhabha Road, Colaba, Mumbai 400005, India.
authors.forename: Anoop
authors.initials: A
authors.lastname: Rawat
authors.affiliation: Institut für Medizinische Physik und Biophysik, Universität Leipzig , Härtelstrasse 16-18, D-04107 Leipzig, Germany.|Institut für Anatomie, Universität Leipzig , Liebigstr. 13, D-04103 Leipzig, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Krueger
authors.affiliation: Institut für Medizinische Physik und Biophysik, Universität Leipzig , Härtelstrasse 16-18, D-04107 Leipzig, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Huster
authors.affiliation: Department of Chemical Science, Tata Institute of Fundamental Research , Homi Bhabha Road, Colaba, Mumbai 400005, India.
authors.forename: Sudipta
authors.identifier: 0000-0002-6540-7472
authors.initials: S
authors.lastname: Maiti
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D066329:Protein Aggregates; D051381:Rats; D012995:Solubility; D013237:Stereoisomerism
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D066329:Protein Aggregates; C078592:amyloid beta-protein (1-40)