Nonspecificity of binding of gamma-secretase modulators to the amyloid precursor protein.
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.
Beel
Andrew J
AJ
Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37232-8725, USA.
Barrett
Paul
P
Schnier
Paul D
PD
Hitchcock
Stephen A
SA
Bagal
Dhanashri
D
Sanders
Charles R
CR
Jordan
John B
JB
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008823:Micelles; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D013379:Substrate Specificity
D016564:Amyloid beta-Protein Precursor; D008823:Micelles; D010446:Peptide Fragments; C441641:amyloid precursor protein carboxyl-terminal fragment gamma; D053829:Amyloid Precursor Protein Secretases