title: C-terminal tetrapeptides inhibit Aβ42-induced neurotoxicity primarily through specific interaction at the N-terminus of Aβ42.
abstract: Inhibition of amyloid β-protein (Aβ)-induced toxicity is a promising therapeutic strategy for Alzheimer's disease (AD). Previously, we reported that the C-terminal tetrapeptide Aβ(39-42) is a potent inhibitor of neurotoxicity caused by Aβ42, the form of Aβ most closely associated with AD. Here, initial structure-activity relationship studies identified key structural requirements, including chirality, side-chain structure, and a free N-terminus, which control Aβ(39-42) inhibitory activity. To elucidate the binding site(s) of Aβ(39-42) on Aβ42, we used intrinsic tyrosine (Y) fluorescence and solution-state NMR. The data suggest that Aβ(39-42) binds at several sites, of which the predominant one is located in the N-terminus of Aβ42, in agreement with recent modeling predictions. Thus, despite the small size of Aβ(39-42) and the hydrophobic, aliphatic nature of all four side-chains, the interaction of Aβ(39-42) with Aβ42 is controlled by specific intermolecular contacts requiring a combination of hydrophobic and electrostatic interactions and a particular stereochemistry.
authors.affiliation: Department of Neurology, David Geffen School of Medicine, Brain Research Institute, University of California, Los Angeles, 635 Charles E. Young Drive South, Los Angeles, California 90095-7334, United States.
authors.forename: Huiyuan
authors.initials: H
authors.lastname: Li
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Du
authors.forename: Dahabada H J
authors.initials: DH
authors.lastname: Lopes
authors.forename: Erica A
authors.initials: EA
authors.lastname: Fradinger
authors.forename: Chunyu
authors.initials: C
authors.lastname: Wang
authors.forename: Gal
authors.initials: G
authors.lastname: Bitan
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D000818:Animals; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D005453:Fluorescence; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D011485:Protein Binding; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010446:Peptide Fragments; C570535:amyloid beta-peptide (39-42); C075222:amyloid beta-protein (1-42); D014443:Tyrosine
references.citation: J Gen Physiol. 2006 Dec;128(6):637-47
references.pmid: 17101816
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14175-80
references.pmid: 18779585
references.citation: J Biol Chem. 2003 Jun 20;278(25):23187-95
references.pmid: 12684519
references.citation: J Alzheimers Dis. 2011;25(4):655-69
references.pmid: 21483096
references.citation: Biochem Biophys Res Commun. 1996 Sep 24;226(3):672-80
references.pmid: 8831674
references.citation: J Mol Biol. 2006 Dec 15;364(5):853-62
references.pmid: 17046788
references.citation: Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):330-5
references.pmid: 12506200
references.citation: Neurology. 2003 Jan 28;60(2):235-9
references.pmid: 12552037
references.citation: Curr Alzheimer Res. 2008 Jun;5(3):319-41
references.pmid: 18537546
references.citation: IUBMB Life. 2007 Apr-May;59(4-5):332-45
references.pmid: 17505973
references.citation: J Med Chem. 2009 Dec 24;52(24):8002-9
references.pmid: 19908889
references.citation: J Med Chem. 2002 Jun 6;45(12):2615-23
references.pmid: 12036371
references.citation: Open Biotechnol J. 2008 Jan 1;2(1):87-93
references.pmid: 19898686
references.citation: J Biol Chem. 2002 Aug 30;277(35):32046-53
references.pmid: 12058030
references.citation: Biochem Biophys Res Commun. 2002 Apr 12;292(4):931-6
references.pmid: 11944904
references.citation: Biochemistry. 1999 Aug 17;38(33):10871-7
references.pmid: 10451383
references.citation: J Neurosci Res. 2002 Sep 1;69(5):567-77
references.pmid: 12210822
references.citation: J Chromatogr A. 2000 Feb 11;869(1-2):171-9
references.pmid: 10720236
references.citation: Science. 2002 Jul 19;297(5580):353-6
references.pmid: 12130773
references.citation: Nat Chem. 2009 Jul;1(4):326-31
references.pmid: 20703363
references.citation: J Biol Chem. 2003 Mar 28;278(13):11612-22
references.pmid: 12499373
references.citation: Biochemistry. 2001 Jul 3;40(26):7882-9
references.pmid: 11425316
references.citation: J Neurochem. 2007 Jun;101(5):1172-84
references.pmid: 17286590
references.citation: Biochim Biophys Acta. 2007 Aug;1768(8):1952-65
references.pmid: 17490607
references.citation: J Biol Chem. 2009 Aug 28;284(35):23580-91
references.pmid: 19567875
references.citation: Biochemistry. 2001 Jul 27;40(28):8237-45
references.pmid: 11444969
references.citation: J Am Chem Soc. 2011 Mar 30;133(12):4348-58
references.pmid: 21381732
references.citation: J Mol Biol. 2011 Jul 8;410(2):316-28
references.pmid: 21621545
references.citation: Neurobiol Dis. 2005 Apr;18(3):499-508
references.pmid: 15755677
references.citation: Annu Rev Cell Dev Biol. 2010;26:211-33
references.pmid: 20500090
references.citation: J Neurochem. 2002 Sep;82(6):1480-9
references.pmid: 12354296
references.citation: Biochemistry. 2006 Oct 17;45(41):12393-9
references.pmid: 17029395
references.citation: J Neurol Neurosurg Psychiatry. 2004 Jul;75(7):1039-42
references.pmid: 15201367
references.citation: Biochemistry. 2010 Aug 3;49(30):6358-64
references.pmid: 20568734
references.citation: Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
references.pmid: 11259830
references.citation: J Biol Chem. 2003 Sep 12;278(37):34882-9
references.pmid: 12840029
references.citation: J Biol Chem. 2000 Aug 18;275(33):25109-15
references.pmid: 10825171
references.citation: Biochemistry. 2010 Feb 16;49(6):1259-67
references.pmid: 20050679
references.citation: J Am Chem Soc. 2010 Mar 31;132(12):4266-80
references.pmid: 20218566
references.citation: J Vis Exp. 2009 Jan 12;(23):
references.pmid: 19229175
references.citation: Biochemistry. 1999 May 25;38(21):6791-800
references.pmid: 10346900
references.citation: Exp Cell Res. 1994 Apr;211(2):314-21
references.pmid: 8143779
references.citation: Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17345-50
references.pmid: 15583128
references.citation: Methods Enzymol. 1999;309:189-204
references.pmid: 10507025
references.citation: Protein Sci. 2005 Jun;14(6):1581-96
references.pmid: 15930005
references.citation: Biochemistry. 2005 Oct 11;44(40):13365-76
references.pmid: 16201761
references.citation: J Biol Chem. 2010 Jul 23;285(30):23186-97
references.pmid: 20452980
references.citation: J Struct Biol. 2000 Jun;130(2-3):130-41
references.pmid: 10940221
references.citation: J Biol Chem. 1996 Apr 12;271(15):8545-8
references.pmid: 8621479
references.citation: Science. 2010 Feb 19;327(5968):973-7
references.pmid: 20110468
references.citation: Proc Natl Acad Sci U S A. 1979 Aug;76(8):3852-6
references.pmid: 291045
references.citation: Acta Neuropathol. 2009 Oct;118(4):487-96
references.pmid: 19547991