title: Impact of membrane lipid composition on the structure and stability of the transmembrane domain of amyloid precursor protein.
abstract: Cleavage of the amyloid precursor protein (APP) by γ-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 C9923-55 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 C9923-55 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 C991-55 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 γ-secretase, critical to the formation of amyloid-β protein, on membrane thickness and lipid composition.
authors: Department of Chemistry, Boston University, Boston, MA 02215; Department of Physical Chemistry, School of Chemistry, National Autonomous University of Mexico, Mexico City 04510, Mexico;
authors: Laura
authors: L
authors: Dominguez
authors: Department of Chemistry, Boston University, Boston, MA 02215;
authors: Leigh
authors: L
authors: Foster
authors: Department of Chemistry, Boston University, Boston, MA 02215; straub@bu.edu.
authors: John E
authors: JE
authors: Straub
authors: Department of Chemistry, University of Texas at Austin, Austin, TX 78712.
authors: D
authors: D
authors: Thirumalai
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics; D019281:Dimerization; D006801:Humans; D008563:Membrane Lipids / Q000737:chemistry* / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry; D011487:Protein Conformation; D000072417:Protein Domains / Q000235:genetics; D055550:Protein Stability; D059748:Proteolysis; D036104:Receptor, EphA2 / Q000737:chemistry / Q000235:genetics*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D008563:Membrane Lipids; D010446:Peptide Fragments; D036104:Receptor, EphA2; D053829:Amyloid Precursor Protein Secretases
keywords: APP dimer; Alzheimer's disease; Aβ peptide; amyloid precursor protein; membrane composition