In this study, Barrett and colleagues unveiled the intriguing structure of the C99 fragment of amyloid precursor protein in bicelles using NMR. They found that the transmembrane domain (TMD) of C99 forms a flexible helix structure bent around glycine (G) residues 708 and 709. Moreover, titration experiments revealed that C99 directly binds cholesterol via GxxxG motifs, which are implicated in TMD dimerization as well as the binding of γ-secretase modulators.

Previous reports suggest that γ-secretase generates Aβ peptides with several C-terminal lengths. Notably, several residues implicated in cholesterol binding correspond to C-terminal residues in most short Aβ species; for example, Gly 704 equates to Aβ33 and G708 to Aβ38 (Page et al., 2010; Kukar et al., 2011). Moreover, alanine substitutions used in this study increased production of short Aβ peptides in cell-based assays (Munter et al., 2007). This suggests the possibility that the efficacy of successive cleavage of APP by γ-secretase is affected by cholesterol binding status of the substrate around GxxxG motifs. In...  Read more

In this study, Barrett and colleagues unveiled the intriguing structure of the C99 fragment of amyloid precursor protein in bicelles using NMR. They found that the transmembrane domain (TMD) of C99 forms a flexible helix structure bent around glycine (G) residues 708 and 709. Moreover, titration experiments revealed that C99 directly binds cholesterol via GxxxG motifs, which are implicated in TMD dimerization as well as the binding of γ-secretase modulators.

Previous reports suggest that γ-secretase generates Aβ peptides with several C-terminal lengths. Notably, several residues implicated in cholesterol binding correspond to C-terminal residues in most short Aβ species; for example, Gly 704 equates to Aβ33 and G708 to Aβ38 (Page et al., 2010; Kukar et al., 2011). Moreover, alanine substitutions used in this study increased production of short Aβ peptides in cell-based assays (Munter et al., 2007). This suggests the possibility that the efficacy of successive cleavage of APP by γ-secretase is affected by cholesterol binding status of the substrate around GxxxG motifs. In other words, this region might be directly involved in the substrate recognition mechanism of the γ-secretase, as the authors suggested in the putative docking model. Further structural analysis of the interaction of APP/γ-secretase would provide a novel strategy for the development of effective γ-secretase modulators.

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