Building alternative splicing and evolution-aware sequence-structure maps for protein repeats

Abstract

Alternative splicing of repeats in proteins provides a mechanism for rewiring and fine-tuning protein interaction networks. In this work, we developed a robust and versatile method, ASPRING, to identify alternatively spliced protein repeats from gene annotations. ASPRING leverages evolutionary meaningful alternative splicing-aware hierarchical graphs to provide maps between protein repeats sequences and 3D structures. We re-think the definition of repeats by explicitly accounting for transcript diversity across several genes/species. Using a stringent sequence-based similarity criterion, we detected over 5,000 evolutionary conserved repeats by screening virtually all human protein-coding genes and their orthologs across a dozen species. Through a joint analysis of their sequences and structures, we extracted specificity-determining sequence signatures and assessed their implication in experimentally resolved and modelled protein interactions. Our findings demonstrate the widespread alternative usage of protein repeats in modulating protein interactions and open avenues for targeting repeat-mediated interactions. Highlights: Robust detection of alternatively used repeated protein regions in evolution The approach relies on sequence similarity and identifies conserved signatures Mapping of the repeats onto protein isoform 3D models predicted by AlphaFold 5 000 repeats detected over the human coding fraction, about one third disordered Assessment of the structural coverage of their interactions with protein partners