| Abstract: |
The high A beta 42/A beta 40 production ratio is a hallmark of familial Alzheimer's disease, which can be caused by mutations in the amyloid precursor protein (APP). The C-terminus of A beta is generated by gamma-secretase cleavage within the transmembrane domain of APP (APPTM), a process that is primed by an initial epsilon-cleavage at either T48 or L49, resulting in subsequent production of A beta 42 or A beta 40, respectively. Here we solve the dimer structures of wild-type APPTM (AAPTM WT) and mutant APPTM (FAD mutants V44M) with solution NMR. The right-handed APPTM helical dimer is mediated by GXXXA motif. From the NMR structural and dynamic data, we show that the V44M and V44A mutations can selectively expose the T48 site by weakening helical hydrogen bonds and increasing hydrogen-deuterium exchange rate (k(ex)). We propose a structural model in which FAD mutations (V44M and V44A) can open the T48 site gamma-secretase for the initial epsilon-cleavage, and consequently shift cleavage preference towards A beta 42. |
