Cholesterol permeable amyloid pores

FIGURE 11.8 How a-helical Api-42 bound to both GMl and cholesterol can form a Ca -permeable amyloid pore. The topology of A(51-42 constrained by both GMl and cholesterol is the same as in Fig. 11.7B. Note that once bound to A(51-42, GMl and cholesterol determine the orientation of Ap inside the membrane. His-13, located at the pore mouth, may attract Ca ions in the channel. The interaction of 7x ions with these residues blocks the channel. 

The other possibility for the formation of an amyloid pore is the insertion of Ap monomers in the membrane, which could be followed by an oligomerization process inside the membrane. Like a-S5muclein, Ap is constrained to adopt an a-helical structure when boimd to lipids. Thus, tiie first step in the formation of an a-structured Ap pore is the interaction of Ap with selected membrane lipids (e.g., ganglioside GMl, which is concentrated in lipid raft domains). In this case, Ap will readily adopt an a-helical conformation (Fig. 11.4). The insertion of a-helical Ap may require the involvement of additional lipids, such as cholesterol, which will also promote the oligomerization process leading to the formation of a functional Ca -permeable pore. As noted by Jang et the a-helical structure of Ap is first formed on the membrane surface. Thus, the insertion of a-helical Ap may require an enei input that can be furnished by the interaction of Ap with cholesterol. In this respect, it is clear ftat the formation of an a-helical oligomeric pore of Ap is strictly dependent upon the presence of specific lipids, especially cholesterol, in the plasma membrane of brain cells. 

FIGURE 8.6 Pore formation by amyloid proteins a membrane-assisted process. Amyloid proteins that have acquired an a-helical structure upon binding to Kpid rafts can penetrate the membrane. The presence of cholesterol rmderneath the glycosphingoHpids (GSL) in lipid raft areas stimulates both the insertion of the protein within the membrane and its oligomerization into Ca -permeable pores. 

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