Katsumi Matsuzaki

Cholesterol-dependent formation of GM1 ganglioside-bound amyloid beta-protein, an endogenous seed for Alzheimer amyloid.

GM1 ganglioside-bound amyloid β-protein (GM1/Aβ), found in brains exhibiting early pathological changes of Alzheimers disease (AD) including diffuse plaques, has been suggested to be involved in the initiation of amyloid fibril formation in vivo by acting as a seed. To elucidate the molecular mechanism underlying GM1/Aβ formation, the effects of lipid composition on the binding of Aβ to GM1-containing lipid bilayers were examined in detail using fluorescent dye-labeled human Aβ-(1–40). Increases in not only GM1 but also cholesterol contents in the lipid bilayers facilitated the binding of Aβ to the membranes by altering the binding capacity but not the binding affinity. An increase in membrane-bound Aβ concentration triggered its conformational transition from helix-rich to β-sheet-rich structures. Excimer formation of fluorescent dye-labeled GM1 suggested that Aβ recognizes a GM1 “cluster” in membranes, the formation of which is facilitated by cholesterol. The results of the present study strongly suggested that increases in intramembrane cholesterol content, which are likely to occur during aging, appear to be a risk factor for amyloid fibril formation.

Elucidation of the Principles of Membrane Protein Folding Using Model Transmembrane Helices.

Hydrophobic lipid bilayer environment constrains transmembrane proteins mostly into an α-helical bundle structure. The folding processes of α-helical transmembrane proteins can be understood in terms of two energetically distinct stages, i.e. 1) independently stable transmembrane helices are formed and 2) the helices interact with each other to give a functional protein. The simplicity of the folding process enables us to use model transmembrane helices for elucidating driving forces working in membrane protein folding in the context of helix-helix interactions. Recent studies have devised several appropriate model peptides that form stable transmembrane helices and just started to quantitatively measure the helix-helix interactions in lipid bilayers. Possible driving forces involved in helix-helix and helix-lipid interactions are summarized. Statistical analyses of structure-known membrane proteins indicate diverse driving forces including the leucine zipper, the GlyXXXGly motif, network of hydrogen bonds and salt bridge.Furthermore, the lipid bilayer environment, which consists of diverse lipid species with asymmetric distributions in inner and outer leaflets, should have substantial effects on helix-helix interactions, therefore on the conformations of the whole proteins.