Structural definition of babesial RAP-1 proteins identifies a novel protein superfamily across Apicomplexa

Authors: ISIDRO, HOTZEL - Genentech; Suarez, Carlos

Submitted to: Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/8/2023
Publication Date: 12/15/2023
Citation: Isidro, H., Suarez, C.E. 2023. Structural definition of babesial RAP-1 proteins identifies a novel protein superfamily across Apicomplexa. Scientific Reports. 13:22330. https://doi.org/10.1038/s41598-023-49532-0.
DOI: https://doi.org/10.1038/s41598-023-49532-0

Interpretive Summary: Apicomplexan protozoa are intracellular parasites of medical and economic importance. These parasites contain specialized apical complex organelles, including rhoptries, that participate in the process of host cell invasion. Conserved antigens expressed in the rhoptries are rational vaccine targets, but whether conservation of protein structure is a functional requirement for invasion remains unknown. Novel protein structural modeling enables identification of structurally conserved protein families that are not evident by sequence analysis alone. In thhis study we analyzed the structure of the well conserved Babesia pRAP-1 proteins and founded that they all contain a similar estructural component known as a "globin domain". Search for structurally related members of this protein family in other apicomplexan parasites revealed prevously unnoticed homologues of pRAP-1 in several species of Plasmodium, Toxoplasma gondii and other members of the Sarcocystidae family. The pRAP-1 is thus the first apical complex protein shown to be widely conserved in different orders of the Apicomplexa. Identification of widely conserved elements involved in infection in these parasites will enhance our knowledge of the mechanisms of invasion and facilitate the design of methods for controlling diseases that affect humans and animals globally.

Technical Abstract: Apicomplexan protozoa are intracellular parasites of medical and economic importance. These parasites contain specialized apical complex organelles, including rhoptries, that participate in the process of host cell invasion. Conserved antigens expressed in the rhoptries are rational vaccine targets, but whether conservation of protein structure is a functional requirement for invasion remains unknown. Novel protein structural modeling enables identification of structurally conserved protein families that are not evident by sequence analysis alone. Here we show by AlphaFold2 structural modeling that the rhoptry-associated protein 1 superfamily of the Piroplasmida hemoparasites Babesia and Theileria (pRAP-1) is structurally conserved, with the core conserved region being composed of a globin-like and a 4-helix bundle subdomain. Search for structurally related members of this protein family in other apicomplexan parasites revealed homologues of pRAP-1 in several species of Plasmodium, Toxoplasma gondii and other members of the Sarcocystidae family. The pRAP-1 is thus the first apical complex protein shown to be widely conserved in different orders of the Apicomplexa. Identification of widely conserved elements involved in infection in these parasites will enhance our knowledge of the mechanisms of invasion and facilitate the design of methods for controlling diseases that affect humans and animals globally.