Impact of membrane lipid composition on the structure and stability of the transmembrane domain of amyloid precursor protein
Por:
Dominguez, Laura, Foster, Leigh, Straub, John E., Thirumalai, D.
Publicada:
6 sep 2016
Categoría:
Multidisciplinary
Resumen:
Cleavage of the amyloid precursor protein (APP) by.-secretase is a
crucial first step in the evolution of Alzheimer's disease. To discover
the cleavage mechanism, it is urgent to predict the structures of APP
monomers and dimers in varying membrane environments. We determined the
structures of the C99(23-55) monomer and homodimer as a function of
membrane lipid composition using a multiscale simulation approach that
blends atomistic and coarse-grained models. We demonstrate that the
C99(23-55) homodimer structures form a heterogeneous ensemble with
multiple conformational states, each stabilized by characteristic
interpeptide interactions. The relative probabilities of each
conformational state are sensitive to the membrane environment, leading
to substantial variation in homodimer peptide structure as a function of
membrane lipid composition or the presence of an anionic lipid
environment. In contrast, the helicity of the transmembrane domain of
monomeric C99(1-55) is relatively insensitive to the membrane lipid
composition, in agreement with experimental observations. The dimer
structures of human EphA2 receptor depend on the lipid environment,
which we show is linked to the location of the structural motifs in the
dimer interface, thereby establishing that both sequence and membrane
composition modulate the complete energy landscape of membrane-bound
proteins. As a by-product of our work, we explain the discrepancy in
structures predicted for C99 congener homodimers in membrane and micelle
environments. Our study provides insight into the observed dependence of
C99 protein cleavage by.-secretase, critical to the formation of
amyloid-beta protein, on membrane thickness and lipid composition.
Filiaciones:
Dominguez, Laura:
Boston Univ, Dept Chem, Boston, MA 02215 USA
Univ Nacl Autonoma Mexico, Sch Chem, Dept Phys Chem, Mexico City 04510, DF, Mexico
Foster, Leigh:
Boston Univ, Dept Chem, Boston, MA 02215 USA
Straub, John E.:
Boston Univ, Dept Chem, Boston, MA 02215 USA
Thirumalai, D.:
Univ Texas Austin, Dept Chem, Austin, TX 78712 USA
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