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Abstract
Brain abundant proteins GAP-43 and BASP1 participate in the regulation of actin cytoskeleton
dynamics in neuronal axon terminals. The proposed mechanism suggests that the proteins
sequester phosphatidylinositol-4,5-diphosphate (PIP(2)) in the inner leaflet of the
plasma membrane. We found that model anionic phospholipid membranes in the form of
liposomes induce rapid oligomerization of GAP-43 and BASP1 proteins. Multiply charged
phosphoinositides produced the most potent effect. Anionic detergent sodium dodecyl
sulfate (SDS) at submicellar concentration stimulated formation of similar oligomers
in solution. BASP1, but not GAP-43, also formed oligomers at sufficiently high concentration
in the absence of lipids and SDS. Electron microscopy study demonstrated that the
oligomers have disk-shaped or annular structure of 10-30nm in diameter. BASP1 also
formed higher aggregates of linear rod-like structure, with average length of about
100nm. In outward appearance, the oligomers and linear aggregates are reminiscent
of oligomers and protofibrils of amyloid proteins. Both the synthetic N-terminal peptide
GAP-43(1-40) and the brain-derived fragment GAP-43-3 preserved the ability to oligomerize
under the action of acidic phospholipids and SDS. On the contrary, BASP1 fragment
truncated by the short N-terminal myristoylated peptide was unable to form oligomers.
GAP-43 and BASP1 oligomerization can be regulated by calmodulin, which disrupts the
oligomers and displaces the proteins from the membrane. We suggest that in vivo, the
role of membrane-bound GAP-43 and BASP1 oligomers consists in accumulation of PIP(2)
in functional clusters, which become accessible for other PIP(2)-binding proteins
after dissociation of the oligomers.