Spatially conserved motifs in complement control protein domains determine functionality in regulators of complement activation-family proteins

摘要

Regulation of complement activation in the host cells is mediated primarily by the regulators of complement activation (RCA) family proteins that are formed by tandemly repeating complement control protein (CCP) domains. Functional annotation of these proteins, however, is challenging as contiguous CCP domains are found in proteins with varied functions. Here, by employing an in silico approach, we identify five motifs which are conserved spatially in a specific order in the regulatory CCP domains of known RCA proteins. We report that the presence of these motifs in a specific pattern is sufficient to annotate regulatory domains in RCA proteins. We show that incorporation of the lost motif in the fourth long-homologous repeat (LHR-D) in complement receptor 1 regains its regulatory activity. Additionally, the motif pattern also helped annotate human polydom as a complement regulator. Thus, we propose that the motifs identified here are the determinants of functionality in RCA proteins. Hina Ojha et al. show that the presence of five motifs in a specific pattern in CCP (complement control protein) domains is indicative of functional RCA (regulators of complement activation) proteins. This study suggests that an in silico regulatory RCA prediction tool CoReDo can be used to identify putative regulatory RCA proteins.