Rational design of disordered proteins for sequence-function investigation.

Authors

Kara Hunter, Trevor Brandt, Karina Guadalupe, Kavindu C Kolamunna, Jeffrey M Lotthammer, Nora M Shamoon, Jessica K Niblo, Brooke Nicholson, Lea M Day, Alec Martinez, Alex S Holehouse, Shahar Sukenik, Ryan J Emenecker

Published in

Nature. Jul 29, 2026. Epub Jul 29, 2026.

Abstract

Despite lacking a stable three-dimensional structure, intrinsically disordered protein regions (IDRs) are ubiquitous across all kingdoms of life and have essential cellular roles¹. While rational design of folded proteins has seen substantial recent progress², our ability to design IDRs remains more limited³. Here we present GOOSE (Generate disOrdered prOteins Specifying propErties), a comprehensive computational framework for the rational design of IDRs. GOOSE's versatility and throughput enable us to design and test thousands of IDR sequences to reveal distinct sequence-to-function relationships. Using GOOSE to explore these relationships, we examine how sequence properties influence IDR structural ensembles in cells, design IDRs that respond to structural changes associated with cell volume decrease, create scaffold IDRs that self-assemble and recruit specific clients, and design novel IDRs that protect cells from desiccation. Our work uses rational sequence design as a powerful method for exploring function in IDRs and provides a versatile tool for designing functional disordered proteins.

PMID:
42527600
Bibliographic data and abstract were imported from PubMed on 30 Jul 2026.

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