Structure of Transmembrane Domain and Dimerization Mechanism of Amyloid Precursor Protein

Abstract

Alzheimer's disease (AD) is the most prevalent form of dementia that affects senior people regardless of religious conviction, nationality or color of skin. The central role in understanding the underlying mechanisms of AD plays biosynthesis of amyloid-β peptide (Aβ). Aβ is a product of sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretase. More than half of mutations that cause so called familial forms of AD are situated in membrane domain of APP and in presenilin-1/presenilin-2 that are part of γ-secretase complex and cleavage APP within the membrane. The pathogenic mutations presumably affect the structure and dynamic properties of the APP transmembrane domain by changing its conformational stability, lateral mobility and /or dimerization. In the present study, the structure of right-handed dimer and dynamics properties of the recombinant peptide corresponding to the APP fragment, Gln686-Lys726, which comprises the APP transmembrane domain with an adjacent N-terminal juxtamembrane sequence, were determined. The structure was solved in the membrane mimetic environment composed of dodecylphosphocholine micelles using NMR spectroscopy. The conformation of transmembrane region each subunit does not alter from published monomer structure. Residues GLY709 and ALA713 form classical GxxxA motif for helix-helix interaction. Juxtamembrane part of investigated peptide does not form tight secondary structure. In this research for the first time dimerization mechanism of APP in atomic resolution is described.