Shanshan Mo # 1, Ruonan Wang # 1, Zhongyi Jian 1, Mingwei Liu 1 2, Feiyi Zhang 1 3, Zhun Deng 1, Wenbo Zhang 1, Yanlian Yang 4, Chen Wang 4, Lanlan Yu 5, Mingzhan Wang 6, Chenxuan Wang 7

Nat Commun. 2026 Jan 6;17(1):1449.

PMID: 41495057 PMCID: PMC12886956 DOI: 10.1038/s41467-025-68185-3

Abstract

β-Strand motifs are essential recognition modules in protein-protein interactions (PPIs), which govern cellular signaling networks and regulate molecular pathway dynamics. Herein we present an unexpected discovery of a previously uncharacterized β-strand insertion mechanism termed as cross-β-strand linking, wherein β-strands within the β-sheet-rich aggregates form inter-β-sheet connections through insertion into adjacent β-sheets. These cross-β-strand linkers comprise <15% of the total β-strands in the amyloidogenic aggregates, but they can mediate a significant proportion of intermolecular interactions, operating as dynamic molecular adapters that regulate the inter-β-sheet packing geometry. Crucially, these linkers exist as conformational ensembles of heterogeneous substates, bestowing remarkable structural diversity to the aggregates. Through promiscuous engagement with multiple conformational substates, cross-β-strand linkers enable the aggregates to balance order and disorder. In this work, we provide a perspective on how low-abundance structural elements can orchestrate complex molecular architectures in assembly systems.

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