Structure of the Monkeypox profilin-like protein A42R reveals potential function differences from cellular profilins

Abstract

The infectious disease human monkeypox is spreading rapidly in 2022 causing a global health crisis. The genomics of the monkeypox virus (MPXV) have been extensively analyzed and reported, although little is known about the virus-encoded proteome. In particular, there is almost no structure information about MPXV proteins, other than computational models. Here we report a 1.52 [A] x-ray structure of the MPXV protein A42R, the only MPXV-encoded protein with a known structure. This protein shows sequence similarity to profilins, which are cellular proteins known to function in regulation of actin cytoskeletal assembly. However, structural comparison of the A42R with known members of the profilin family reveals critical differences that support prior biochemical findings that this protein only weakly binds actin and does not bind poly(L-proline). In addition, the analysis suggests that this protein may have distinct interactions with phosphatidylinositol lipids. Overall, our data suggest that the role of A42R in replication of orthopoxviruses may not be easily determined by comparison to cellular profilins. Further, our findings support a need for increased efforts to determine high-resolution structures of other MPXV proteins to inform physiological studies of the poxvirus infection cycle and to reveal potential new strategies to combat human monkeypox should the infection become more common in the future.