Nonspecificity of binding of gamma-secretase modulators to the amyloid precursor protein.

Beel AJ, Barrett P, Schnier PD, Hitchcock SA, Bagal D, Sanders CR, Jordan JB
Biochemistry. 2009 48 (50): 11837-9

PMID: 19928774 · PMCID: PMC2794937 · DOI:10.1021/bi901839d

Evidence that certain gamma-secretase modulators (GSMs) target the 99-residue C-terminal domain (C99) of the amyloid precursor protein, a substrate of gamma-secretase, but not the protease complex itself has been presented [Kukar, T. L., et al. (2008) Nature 453, 925-929]. Here, NMR results demonstrate a lack of specific binding of these GSMs to monodisperse C99 in LMPG micelles. In addition, results indicate that C99 was likely to have been aggregated in some of the key experiments of the previous work and that binding of GSMs to these C99 aggregates is also of a nonspecific nature.

MeSH Terms (10)

Alzheimer Disease Amino Acid Sequence Amyloid beta-Protein Precursor Amyloid Precursor Protein Secretases Humans Micelles Molecular Sequence Data Peptide Fragments Protein Binding Substrate Specificity

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