Formation of extramembrane β-strands controls dimerization of transmembrane helices in amyloid precursor protein C99.

ABSTRACT: The 99-residue C-terminal domain of amyloid precursor protein (APP-C99), precursor to amyloid beta (Aβ), is a transmembrane (TM) protein containing intrinsically disordered N- and C-terminal extramembrane domains. Using molecular dynamics (MD) simulations, we show that the structural ensemble of the C99 monomer is best described in terms of thousands of states. The C99 monomer has a propensity to form β-strand in the C-terminal extramembrane domain, which explains the slow spin relaxation times observed in paramagnetic probe NMR experiments. Surprisingly, homodimerization of C99 not only narrows the conformational ensemble from thousands to a few states through the formation of metastable β-strands in extramembrane domains but also stabilizes extramembrane α-hel

SUBMITTER: Pantelopulos GA 

PROVIDER: S-EPMC9907117 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature