Rapid formation of peptide/lipid co-aggregates by the amyloidogenic seminal peptide PAP248-286
AbstractProtein/lipid co-assembly is an understudied phenomenon that is important to the function of antimicrobial peptides as well as the pathological effects of amyloid. Here we study the co-assembly process of PAP248-286, a seminal peptide that displays both amyloid-forming and antimicrobial activity. PAP248-286 is a fragment of prostatic acid phosphatase and has been reported to form amyloid fibrils, known as semen-derived enhancer of viral infection (SEVI), that enhance the viral infectivity of HIV. We find that in addition to forming amyloid, PAP248-286 much more readily assembles with lipid vesicles into peptide/lipid co-aggregates that resemble amyloid fibrils in some important ways but are a distinct species. The formation of these co-aggregates, which we term “messicles”, is controlled by the peptide:lipid (P:L) ratio and by the lipid composition. The optimal P:L ratio is around 1:10 and at least 70% anionic lipid is required for co-aggregate formation. Once formed, messicles are not disrupted by subsequent changes in P:L ratio. We propose that messicles form through a polyvalent assembly mechanism, where a critical surface density of PAP248-286 on liposomes enables peptide-mediated particle bridging into larger species. Even at ~100-fold lower PAP248-286 concentrations, messicles form at least 10-fold faster than amyloid fibrils. It is therefore possible that, some or all of the biological activities assigned to SEVI, the amyloid form of PAP248-286, could instead be attributed to a PAP248-286/lipid co-aggregate. More broadly speaking, this work provides a potential framework for the discovery and characterization of peptide/lipid co-aggregates by other amyloid-forming proteins and antimicrobial peptides.Statement of SignificancePAP248-286, a fragment of prostatic acid phosphatase, forms amyloid thought to enhances the infectivity of many viruses, including HIV. This amyloid, termed semen-derived enhancer of viral infection (SEVI), has been assigned responsibility for all of PAP248-286’s biological activities, while the monomer is thought to be inactive. However, SEVI formation is quite slow and requires very high concentrations of PAP248-286. Here, we show that PAP248-286 can instead assemble much more rapidly with lipid membranes to form another species, mechanistically and morphologically distinct from both monomer and SEVI amyloid. We have characterized this new species, which could play a role in the biological activities currently ascribed to SEVI. Additionally, our proposed mechanism for peptide/lipid co-assembly could apply to other biologically important systems.
