Insights into the functional expansion of the astacin peptidase family in parasitic helminths

Abstract

Helminths secrete a plethora of proteins involved in parasitism-related processes such as tissue penetration, migration, feeding and immunoregulation. Astacins, a family of zinc metalloproteases belonging to the peptidase family M12, are one of the most abundantly represented protein families in the secretomes of helminths. Despite their involvement in virulence, very few studies have addressed the role of this loosely defined protein group in parasitic helminths. Herein, we have analysed the predicted proteomes from 154 helminth species and confirmed the expansion of the astacin family in several nematode taxa. The astacin domain associated with up to 110 other domains into 145 unique domain architectures, where CUB and ShK constitute the principal and nearly independent bi-domain frameworks. The presence of co-existing domains suggests promiscuous adaptable functions to several roles. These activities could be related either to substrate specificity or to higher-order functions, such as anti-angiogenesis and immunomodulation, where the astacin domain would play an accessory role. Furthermore, some phylogenetically restricted mutations in the astacin domain affected residues located at the active cleft and binding sub-pockets, suggesting adaptation to different substrate specificities. Altogether, these findings suggest the astacin domain is a highly adaptable module that fulfils multiple proteolytic needs of the parasitic lifestyle. This study contributes to the understanding of helminth-secreted astacins and, ultimately, provides the foundation to guide future investigations about the role of this diverse family of proteins in host–parasite interactions.