The effect of sequence and environment on the structure and dimerization of amyloid precursor protein
Foster, Leigh Suzanne Holmes
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Aggregation of amyloid β (Aβ) protein has been linked to the development of Alzheimer's Disease (AD). The genesis of Aβ involves the cleavage Amyloid Precursor Protein (APP) by β-secretase, producing the 99-residue C99 peptide, and the subsequent cleavage of C99 by γ-secretase to produce Aβ. A detailed understanding of the γ-cleavage process is essential to our undertsanding of the pathological mechanisms linking the aggregation of Aβ to the development of AD. This work seeks to provide insight into critical aspects of the structure and dynamics of C99, and the particular roles played by (1) C99 amino acid sequence and (2) the lipid composition of the membrane environment. Many studies have focused on the importance of the C99 sequence, including known studies of Familial AD (FAD) mutants as well as engineered mutations. Specific mutations have been found to affect the processing of C99, which has been linked to changes in the structure of C99 and the formation of C99 homodimers. Similarly, changes in the membrane environment, through variation in lipid composition and the presence of cholesterol, have been found to affect C99 structure and positioning within the membrane as well as C99 dimerization. The results of this work extend our understanding of the APP-C99 system and its interaction with the environment. Using a multiscale simulation approach, we find key structural effects of engineered mutations that suggest possible mechanistic insight into the γ-cleavage process. Using C99 congener peptides, we examine the effect of local membrane environment on the dimerization of C99, focusing on the roles of both the transmembrane (TM) region as well as the juxtamembrane (JM) domain. Further studies characterize the role of a FAD mutation, and demonstrate the effect of the mutation on the dimerization of C99 in agreement with experimental findings. Overall, this work leads to critical insight into the role of sequence and membrane on the structure of C99 in a membrane environment, and provides support for the conjecture that the structure of C99 monomer and homodimer are critical to our understanding of the processing of C99, a critical step in the genesis of Aβ peptide and the etiology of Alzheimer's Disease.