No abstract

Background: Two alleles of the mammalian Ras protein acyltransferase are associated with X-linked intellectual disabilities. Results: Mutations of zDHHC9 isolated from XLID patients result in defects to steady state autopalmitoylation levels. Conclusion: Although the zDHHC9 mutations produce similar phenotypes, they are guided by distinct mechanisms. Significance: Elucidation of the catalytic mechanism of PATs is a critical step in designing pharmacological interventions.

Protein intrinsic disorder is an important characteristic demonstrated by the absence of higher order structure, and is commonly detected in multifunctional proteins encoded by RNA viruses. Intrinsically disordered regions (IDRs) of proteins exhibit high flexibility and solvent accessibility, which permit several distinct protein functions, including but not limited to binding of multiple partners and accessibility for post-translational modifications. IDR-containing viral proteins can therefore execute various functional roles to enable productive viral replication. Respiratory syncytial virus (RSV) is a globally circulating, non-segmented, negative sense (NNS) RNA virus that causes severe lower respiratory infections. In this study, we performed a comprehensive evaluation of predicted intrinsic disorder of the RSV proteome to better understand the functional role of RSV protein IDRs. We included 27 RSV strains to sample major RSV subtypes and genotypes, as well as geographic and temporal isolate differences. Several types of disorder predictions were applied to the RSV proteome, including per-residue (PONDR®-FIT and PONDR® VL-XT), binary (CH, CDF, CH-CDF), and disorder-based interactions (ANCHOR and MoRFpred). We classified RSV IDRs by size, frequency and function. Finally, we determined the functional implications of RSV IDRs by mapping predicted IDRs to known functional domains of each protein. Identification of RSV IDRs within functional domains improves our understanding of RSV pathogenesis in addition to providing potential therapeutic targets. Furthermore, this approach can be applied to other NNS viruses that encode essential multifunctional proteins for the elucidation of viral protein regions that can be manipulated for attenuation of viral replication.