TY - JOUR
T1 - A Critical Role of Ser26 Hydrogen Bonding in Aβ42 Assembly and Toxicity
AU - Roychaudhuri, Robin
AU - Huynh, Tien Phat V.
AU - Whitaker, Taylor R.
AU - Hodara, Elisabeth
AU - Condron, Margaret M.
AU - Teplow, David B.
N1 - Funding Information:
*E-mail: dteplow@mednet.ucla.edu. ORCID David B. Teplow: 0000-0002-2389-3417 Present Addresses §R.R.: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205. ∥T.-P.V.H.: Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Author Contributions R.R. and D.B.T. designed the experiments. M.M.C. synthesized the peptides. R.R., T.-P.V.H., T.R.W., and E.H. performed the experiments. R.R., T.-P.V.H., T.R.W., E.H., and D.B.T. analyzed the data. All authors contributed to the writing of the manuscript. Funding National Institutes of Health Grants AG042195 and NS038328 to D.B.T. Notes The authors declare no competing financial interest.
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/12/5
Y1 - 2017/12/5
N2 - Amyloid β-protein (Aβ) assembly is a seminal process in Alzheimer's disease. Elucidating the mechanistic features of this process is thought to be vital for the design and targeting of therapeutic agents. Computational studies of the most pathologic form of Aβ, the 42-residue Aβ42 peptide, have suggested that hydrogen bonding involving Ser26 may be particularly important in organizing a monomer folding nucleus and in subsequent peptide assembly. To study this question, we experimentally determined structure-activity relationships among Aβ42 peptides in which Ser26 was replaced with Gly, Ala, α-aminobutryic acid (Abu), or Cys. We observed that aliphatic substitutions (Ala and Abu) produced substantially increased rates of formation of β-sheet, hydrophobic surface, and fibrils, and higher levels of cellular toxicity. Replacement of the Ser hydroxyl group with a sulfhydryl moiety (Cys) did not have these effects. Instead, this peptide behaved like native Aβ42, even though the hydropathy of Cys was similar to that of Abu and very different from that of Ser. We conclude that H bonding of Ser26 is the factor most important in its contribution to Aβ42 conformation, assembly, and subsequent toxicity.
AB - Amyloid β-protein (Aβ) assembly is a seminal process in Alzheimer's disease. Elucidating the mechanistic features of this process is thought to be vital for the design and targeting of therapeutic agents. Computational studies of the most pathologic form of Aβ, the 42-residue Aβ42 peptide, have suggested that hydrogen bonding involving Ser26 may be particularly important in organizing a monomer folding nucleus and in subsequent peptide assembly. To study this question, we experimentally determined structure-activity relationships among Aβ42 peptides in which Ser26 was replaced with Gly, Ala, α-aminobutryic acid (Abu), or Cys. We observed that aliphatic substitutions (Ala and Abu) produced substantially increased rates of formation of β-sheet, hydrophobic surface, and fibrils, and higher levels of cellular toxicity. Replacement of the Ser hydroxyl group with a sulfhydryl moiety (Cys) did not have these effects. Instead, this peptide behaved like native Aβ42, even though the hydropathy of Cys was similar to that of Abu and very different from that of Ser. We conclude that H bonding of Ser26 is the factor most important in its contribution to Aβ42 conformation, assembly, and subsequent toxicity.
UR - http://www.scopus.com/inward/record.url?scp=85038125037&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85038125037&partnerID=8YFLogxK
U2 - 10.1021/acs.biochem.7b00772
DO - 10.1021/acs.biochem.7b00772
M3 - Article
C2 - 29140083
AN - SCOPUS:85038125037
SN - 0006-2960
VL - 56
SP - 6321
EP - 6324
JO - Biochemistry
JF - Biochemistry
IS - 48
ER -