TY - JOUR
T1 - Dual concentration-dependent effect of ascorbic acid on PAP(248-286) amyloid formation and SEVI-mediated HIV infection
AU - Mohapatra, Satabdee
AU - Viswanathan, Guru Krishna Kumar
AU - Wettstein, Lukas
AU - Arad, Elad
AU - Paul, Ashim
AU - Kumar, Vijay
AU - Jelinek, Raz
AU - Münch, Jan
AU - Segal, Daniel
N1 - Publisher Copyright:
© The Royal Society of Chemistry.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - Human semen contains various amyloidogenic peptides derived from Prostatic Acid Phosphatase (PAP) and Semenogelin proteins that are capable of enhancing HIV-1 infection when assembled into fibrils. The best characterized among them is a 39 amino acid peptide PAP(248-286), which forms amyloid fibrils termed SEVI (semen-derived enhancer of viral infection) that increase the infectivity of HIV-1 by orders of magnitude. Inhibiting amyloid formation by PAP(248-286) may mitigate the sexual transmission of HIV-1. Several vitamins have been shown to reduce the aggregation of amyloids such as Aβ, α-Synuclein, and Tau, which are associated with neurodegenerative diseases. Since ascorbic acid (AA, vitamin C) is the most abundant vitamin in semen with average concentrations of 0.4 mM, we here examined how AA affects PAP(248-286) aggregation in vitro. Using ThT binding assays, transmission electron microscopy, and circular dichroism spectroscopy, a dual and concentration-dependent behavior of AA in modulating PAP(248-286) fibril formation was observed. We found that low molar ratios of AA:PAP(248-286) promoted whereas high molar ratios inhibited PAP(248-286) fibril formation. Accordingly, PAP(248-286) aggregated in the presence of low amounts of AA enhanced HIV-1 infection, whereas excess amounts of AA during aggregation reduced the infectivity enhancing effect in cell culture. Collectively, this work provides a biophysical insight into the effect of AA, an important seminal component, on SEVI fibrillation which might impact amyloid formation kinetics, thereby modulating the biological activity of semen amyloids.
AB - Human semen contains various amyloidogenic peptides derived from Prostatic Acid Phosphatase (PAP) and Semenogelin proteins that are capable of enhancing HIV-1 infection when assembled into fibrils. The best characterized among them is a 39 amino acid peptide PAP(248-286), which forms amyloid fibrils termed SEVI (semen-derived enhancer of viral infection) that increase the infectivity of HIV-1 by orders of magnitude. Inhibiting amyloid formation by PAP(248-286) may mitigate the sexual transmission of HIV-1. Several vitamins have been shown to reduce the aggregation of amyloids such as Aβ, α-Synuclein, and Tau, which are associated with neurodegenerative diseases. Since ascorbic acid (AA, vitamin C) is the most abundant vitamin in semen with average concentrations of 0.4 mM, we here examined how AA affects PAP(248-286) aggregation in vitro. Using ThT binding assays, transmission electron microscopy, and circular dichroism spectroscopy, a dual and concentration-dependent behavior of AA in modulating PAP(248-286) fibril formation was observed. We found that low molar ratios of AA:PAP(248-286) promoted whereas high molar ratios inhibited PAP(248-286) fibril formation. Accordingly, PAP(248-286) aggregated in the presence of low amounts of AA enhanced HIV-1 infection, whereas excess amounts of AA during aggregation reduced the infectivity enhancing effect in cell culture. Collectively, this work provides a biophysical insight into the effect of AA, an important seminal component, on SEVI fibrillation which might impact amyloid formation kinetics, thereby modulating the biological activity of semen amyloids.
UR - http://www.scopus.com/inward/record.url?scp=85116859036&partnerID=8YFLogxK
U2 - 10.1039/d1cb00084e
DO - 10.1039/d1cb00084e
M3 - Article
C2 - 34704058
AN - SCOPUS:85116859036
SN - 2633-0679
VL - 2
SP - 1534
EP - 1545
JO - RSC Chemical Biology
JF - RSC Chemical Biology
IS - 5
ER -