Protein fold diversity and evolution in Archaea: from adaptation to extreme environments to the origin of eukaryotes – DArchFolds

Characterizing how environmental pressures have shaped the diversity of protein folds and functions is essential to understand the evolution of biodiversity. Proteins are molecular Legos of protein bricks whose combination dictates the protein fold and function. Is the inventory of known protein bricks and folds complete? What are the main sources of protein diversity? How do environmental constraints shape the protein structural space? These are fundamental questions to understand the structural bases of molecular innovation and species adaptation. In this project, we focus on the protein diversity in archaea (inferred from complete genomes and metagenome-assembled genomes (MAGS)) from a wide variety of habitats, including extreme ones. Encoding many ORFan genes (i.e., lacking homologs in other species), and being poorly studied, they are expected to potentially uncover new protein folds and bricks. Until recently, characterizing the fold diversity in these proteomes was unthinkable due to the time and resources required to solve even a single protein structure. However, the recent DeepMind's program AlphaFold2 has revolutionized structural biology with an artificial intelligence network able to predict 3D protein structures from amino-acid sequences with unrivaled atomic accuracy. This offers an unprecedented opportunity to (1) answer the old open question: do we know all protein bricks and folds existing in nature? and (2) study the relationship between environmental constraints and the 3D repertoire of protein bricks, folds and functions. We will address these questions by exploring a large dataset of 500 archaeal genomes and MAGS selected to cover the archaeal tree of life and ecosystem types, along with their protein fold annotation. These will reveal molecular adaptive innovations to their environment. Finally, we will investigate if eukaryotes share more protein bricks and folds with the Asgard archaea, the seemingly closest archaeal relatives of eukaryotes.