Structural Heterogeneity in Transmembrane Amyloid Precursor Protein Homodimer Is a Consequence of Environmental Selection

The
99 amino acid C-terminal fragment of amyloid precursor protein
(C99), consisting of a single transmembrane (TM) helix, is known to
form homodimers. Homodimers can be processed by γ-secretase
to produce amyloid-β (Aβ) protein, which is implicated
in Alzheimer’s disease (AD). While knowledge of the structure
of C99 homodimers is of great importance, experimental NMR studies
and simulations have produced varying structural models, including
right-handed and left-handed coiled-coils. In order to investigate
the structure of this critical protein complex, simulations of the
C9915–55 homodimer in POPC membrane bilayer and
DPC surfactant micelle environments were performed using a multiscale
approach that blends atomistic and coarse-grained models. The C9915–55 homodimer adopts a dominant right-handed coiled-coil
topology consisting of three characteristic structural states in a
bilayer, only one of which is dominant in the micelle. Our structural
study, which provides a self-consistent framework for understanding
a number of experiments, shows that the energy landscape of the C99
homodimer supports a variety of slowly interconverting structural
states. The relative importance of any given state can be modulated
through environmental selection realized by altering the membrane
or micelle characteristics.