Proteome-wide comparison of tertiary protein structures reveals molecular mimicry in -human interactions.

INTRODUCTION

Molecular mimicry is a strategy used by parasites to evade the host's immune system and facilitate transmission to a new host. To date, high-throughput examples of molecular mimicry have been limited to comparing protein sequences. However, recent advances in the prediction of tertiary structural models, led by Deepmind's AlphaFold, enable the comparison of thousands of proteins from parasites and their hosts at the structural level, allowing for the identification of more mimics. Here, we present the first proteome-level search for tertiary structure similarity between proteins from , a malaria-causing parasite, and humans.

METHODS

We assembled a database of experimentally-characterized protein tertiary structures (from the Protein Data Bank) and AlphaFold-generated protein tertiary structures from , human, and 15 negative control species, ., species not infected by . We aligned human and control structures to the parasite structures using Foldseek.

RESULTS

We identified molecular mimicry in three proteins that have been previously proposed as mediators of -human interactions. By extending this approach to all proteins, we identified an additional 41 potential mimics that are supported by additional experimental data.

DISCUSSION

Our findings demonstrate a valuable application of AlphaFold-derived tertiary structural models, and we discuss key considerations for its effective use in other host-parasite systems.