Implications of intrinsic disorder and functional proteomics in the merkel cell polyomavirus life cycle.

Abstract

Infection with merkel cell polyomavirus (MCPyV) is implicated in the development of merkel cell carcinoma (MCC), a rare but aggressive skin cancer. MCC has a mortality rate near 50%, and incidence has been rapidly increasing in recent decades, making development of improved treatment strategies critical to addressing its growing social burden. The parallel increasing necessity for novel research to better understand MCPyV pathogenesis has prompted numerous studies in recent years, yet the role of intrinsic disorder in MCPyV proteins remains unexplored. This study carries out computational characterization of intrinsic disorder within the MCPyV proteome and suggests mechanisms that may contribute to the oncogenicity of the virus to invade and hijack host immune systems. Our analysis finds that significant levels of intrinsic disorder are present in proteins LT, ALTO, 57kT, and VP1, and suggests that regions of sT may also contain large, disordered regions. The investigation further shows correlation of disorder propensity with the outputs for functional predictors of eukaryotic linear motifs (ELMs), molecular recognition features (MoRFs), and propensity for liquid-liquid phase separation (LLPS). Our findings indicate that MCPyV may use disorder and phase condensation to alter viral function that may accentuate or provide the basis for oncogenic activities. It is intended that this study will inform future experimental validation efforts around the phase separation capacity of MCPyV and its host protein-protein interactions. Furthermore, we hope to inform other investigators on the potential role of disorder in the MCPyV life cycle toward ultimately progressing the development of novel therapeutic agents.