Amino acid repeat mosaics shape protein functional landscape

How combinations of functional units such as repeats and motifs within disordered regions influence protein functions remains poorly understood. Here, we investigate how co-occurring amino acid homorepeats of different types within the same protein (HR-mosaics) shape molecular outcomes. Using a novel evolutionary co-occurrence metric, human HR-mosaics were classified as segregated (each HR independently influences distinct outcomes), concerted-disjunct (both HRs jointly shape protein functionality without modulating each other), or concerted-conjunct (both HRs affect functionality through mutual influence). Molecular studies of naturally occurring polyGly-polyPro mosaic in DDX17 and chimeric mosaics of polyAla and polyHis demonstrate that HR-mosaics influence protein abundance, localisation, mobility and interaction landscape. Segregated HR-mosaics expand functional space, concerted-disjunct additionally confer biological context, and concerted-conjunct mosaics further enable rheostatic regulation between HRs. These design principles underscore amino acid type, length and relative positioning of HRs as central architects of HR-mosaic functionality, with implications in protein design and engineering and understanding repeat-associated pathologies.