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bioRxiv · 10.64898/2026.06.09.730932

Amino acid repeat mosaics shape protein functional landscape

Singh, A.·Babu, A.·Gopalakrishnan, A.·Rachote, N.·Sharma, V.·Ganguli, S.·Kappagantula, K.·Ramadasan, H.·Shukla, P.·Dhayalan, A.·Chavali, P.·Chavali, S.
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Abstract

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.

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Singh, A., Babu, A., Gopalakrishnan, A., Rachote, N., Sharma, V., Ganguli, S., Kappagantula, K., Ramadasan, H., Shukla, P., Dhayalan, A., Chavali, P., Chavali, S.. 2026-06-12. Amino acid repeat mosaics shape protein functional landscape. https://doi.org/10.64898/2026.06.09.730932

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