Insights into the interaction of the N-terminal amyloidogenic polypeptide of ApoA-I with model cellular membranes

Giulia Rusciano, Giuseppe Pesce, Gianluigi Zito, Antonio Sasso, Rosa Gaglione, Rita Del Giudice, Renata Piccoli, Daria Maria Monti, Angela Arciello

About twenty variants of apolipoprotein A-I (ApoA-I) are associated to hereditary systemic amyloidoses. Although the molecular bases of this disease are still largely unknown, it has been hypothesized that ApoA-I proteolysis is a key event in pathogenesis, since it triggers the release of an N-terminal fragment (80–100 residue long) that misfolds to form amyloid deposits in peripheral organs and tissues. It is also known that cell membrane lipids play a key role in the fibrillogenic pathway. In the case of ApoA-I related amyloidosis caused by L174S mutation, the 93-residue N-terminal fragment of ApoA-I ([1-93]ApoA-I) was found to be the major constituent of ex vivo fibrils. With the main goal to investigate the interaction of either [1-93]ApoA-I and ApoA-I with biomimetic membranes, we set-up an experimental system based on the Raman Tweezers methodology. We tested GUVs composed by two types of zwitterionic lipids with a different fluidity degree, i.e. dioleoylphosphatidylcholine (DOPC) and dipalmitoylphosphatidylcholine (DPPC). We found that [1-93]ApoA-I induces conformational disorder in an ordered lipid bilayer. When interacting with fluid phases, instead, the fragment was found to be able to penetrate the membrane bilayer inducing an alignment of lipid chains. The interaction features of [1-93]ApoA-I with biomimetic membranes strongly depend on the lipid phase. Full-length ApoA-I was found to have similar effects, even if significantly less pronounced. Our observations shed light on still largely unknown molecular bases of ApoA-I fibrillogenic domain interaction with membranes.

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