The evolutionary link between Coccidian SRS proteins and the malarial "6-Cys Domain" family : new clues from modeled 3-D structures


Dietlind L Gerloff*, Edward Liaw, Eli Draizen, David S Hall, Jonathan Magasin, Felicia Kemp, Richard Carter


Earlier this year a fragment 3-D structure of the malarial surface protein Pf12 was solved by NMR spectroscopy (Arredondo et al., PNAS 109:6692-6697, 2012). This confirmed our prediction of a distant evolutionary relationship between the "6-Cys Domain" antigens in Plasmodia with the Coccidian SRS (SAG1-Related Sequences), and validated the "first generation" structural models from 2005 (Gerloff et al., PNAS 102:13598-13603). Fold similarity between surface proteins can be difficult to detect, especially in pathogens, due to highly variable insertions, etc. Here the characteristic connectivity between the 6 cysteines is distinct in either family, also their characterized functions so far are generally different. The malarial gametocyte proteins Pfs48/45 and Pfs230 are transmission-blocking vaccine candidates built from "6-Cys domains". Instances of this domain are annotated in related species, e.g. Babesia, but not yet outside the Hemosporidia. If anything besides fold resemblance had remained of their common ancestry with the dominant SRS antigen family in the tissue-cyst forming Coccidia, this could potentially accelerate target selection for disease intervention.

Looking for clues to their history, we screened 102,878 predicted proteins from Apicomplexan genomes sensitively with merged family HMMs (hidden Markov Models). The more complete map of occurrences of this Apicomplexa-specific β-sandwich fold (>2,500 plausibly aligned domain matches) provides a glimpse of their evolutionary basis, structurally (and possibly functionally). For example we found 9 in Theileria species which currently lack any annotated 6-Cys Domain proteins. In the Coccidia (Toxoplasma/Neospora/Sarcocystis) we found newly evolved cysteine positions and most strikingly, a candidate "evolutionary link" protein, with unusual resemblance to the homologs in the Plasmodia/Piroplasmida.

All updated 3-D structural models are available in our 6-Cys Domain Model Database