Structures of β-Amyloid Peptide 1−40, 1−42, and 1−55—the 672−726 Fragment of APP—in a Membrane Environment with Implications for Interactions with γ-Secretase

Abstract

Aggregation Amyloid β (Aβ) peptide has been linked to the neurodegenerative Alzheimer's Disease and implicated in other amyloid diseases including cerebral amyloid angiopathy. Aβ peptide is generated by cleavage of the amyloid precursor protein (APP) by transmembrane proteases. It is crucial to determine the structures of β-amyloid peptides in a membrane to provide a molecular basis for the cleavage mechanism. We report the structures of amyloid β peptide (Aβ 1-40 and Aβ 1-42 ) as well as the 672-726 fragment of APP (referred to as Aβ 1-55 ) in a membrane environment determined by replica-exchange molecular dynamics simulation. Aβ 1-40 is found to have two helical domains A (13-22) and B(30-35) and a type I β turn at 23-27. The peptide is localized at the interface between membrane and solvent. Substantial fluctuations in domain A are observed. The dominant simulated tertiary structure of Aβ 1-40 is observed to be similar to the simulated Aβ 1-42 structure. However, there are differences observed in the overall conformational ensemble as characterized by the twodimensional free energy surfaces. The fragment of APP (Aβ 1-55 ) is observed to have a long transmembrane helix. The position of the transmembrane region and ensemble of membrane structures are elucidated. The conformational transition between the transmembrane Aβ 1-55 structure, prior to cleavage, and the Aβ 1-40 structure, following cleavage, is proposed.

Impact of membrane lipid composition on the structure and stability of the transmembrane domain of amyloid precursor protein

“…Gly 37 /Gly 38 (19). This key prediction was validated in a recent study involving H/D exchange experiments on the C99 peptide complemented with molecular dynamics (MD) simulations of the TM region, C99 28−55 , in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer (20), which also provided detailed insights into the stability of the TM helical region of C99.…”

Biochemistry of Amyloid -Protein and Amyloid Deposits in Alzheimer Disease

“…There has been a longstanding controversy in the field as to whether this re-insertion event leads to the formation of a complete transmembrane pore or whether membrane association and partial insertion can disrupt the bilayer to such an extent that its structural integrity is compromised. MD simulations and in vitro artificial lipid membrane models of this insertional event are plentiful (Friedman et al 2009;Lemkul and Bevan 2009;Miyashita et al 2009;Qiu et al 2009;Song et al 2009;Yang et al 2009a,b;Morita et al 2010;Schauerte et al 2010;Wang et al 2010), but rigorous evidence for a hydrophobic membrane-traversing interaction in vivo is lacking. Using photobleaching Förster resonance energy transfer, there was a loss of signal from the hydrophobic carboxyl terminus of Ab as it interacts with the plasma membrane of PC12 cells, which may indicate its sequestration within the lipid bilayer (Bateman and Chakrabartty 2009).…”

Dimeric structure of transmembrane domain of amyloid precursor protein in micellar environment

“…Moreover, all the various dimerization motifs can be functionally relevant in different circumstances, such as local lipidic composition of the membrane, surface pH, or interaction with other membrane-bound proteins, especially since our present knowledge of APP functions is not exhaustive. The observed kink of the TM-helix can serve for adapting APP TM domain structure to the membrane thickness [23], allowing for different dimerization modes to be realized in appropriate conditions. The sequential c-secretase cleavage (occurring in the vicinity of lipid polar heads) can initiate transitions between various dimerization modes, or even cause new modes to appear as a result of sinking of the N-terminal JM region, which contains an additional GG4-motif G 696 AIIG 700 , into the membrane.…”