Pangenome-scale annotation of mycobacteriophages for dissecting phage–host interactions based on a sequence clustering and structural homology analysis strategy

Abstract

Mycobacteriophages constitute the largest group of phages with sequenced genomes. However, a significant portion of these phage proteins have not yet been effectively annotated, seriously hindering our understanding of the basic biological processes of phage–host interactions and their practical applications. This study utilized a structure-based similarity search approach to enhance phage protein annotation. This approach led to the identification of novel predicted protein folds, structural domain fusion phenomena, and putative new enzymes. Additionally, the study identified a series of phage-encoded proteins that may play a role in hijacking host-associated replication, transcription, and translation processes, providing insights into the molecular mechanisms underlying mycobacteriophage interactions with host machinery. This study addresses a critical knowledge gap regarding the potential function of phage proteins and provides key insights into the interactions between mycobacteriophages and their hosts.