Abstract

The ability of human encoded soluble proteins to convert into amyloid fibrils is now recognized as a generic phenomenon in several human illnesses. Typically, such disease causal proteins/peptides consist of aggregation-prone regions (APR) that make them susceptible to misfolding and assemble into highly ordered {beta}-sheet rich fibrils, distinct from their native soluble state. Here, we show that the zika virus (ZIKV) consists of several such aggregation prone hotspots spread across its entire proteome. Using a combination of high-accuracy prediction tools, we identified APRs in both structural and non-structural proteins of ZIKV. Furthermore, we have experimentally validated the bioinformatic results by subjecting the ZIKV proteins and peptides to artificial aggregation inducing environment. Using a combination of dye-based assays (ThT and ANS) and microscopy techniques (HR-TEM and AFM), we further characterized the morphological features of amyloid-like fibrils. We found that Envelope domain III (EDIII) protein, NS1 {beta}-roll peptide, membrane-embedded signal peptide 2K, and cytosolic region of NS4B protein to be highly aggregating in the experimental setup. Our findings also pave the way for an extensive and detailed functional analysis of these predicted APRs in the future to enhance our understanding of the role played by amyloids in the pathogenesis of flavivirus. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/485915v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1bedf4dorg.highwire.dtl.DTLVardef@364676org.highwire.dtl.DTLVardef@14bf54aorg.highwire.dtl.DTLVardef@1d4fc19_HPS_FORMAT_FIGEXP M_FIG C_FIG