Trioxane-based MS-cleavable cross-linking mass spectrometry for profiling multimeric interactions of cellular networks

Clinton Yu, Eric Novitsky, Sree Ganesh Balasubramani, Xiaorong Wang, Xiyu Shen, Qin Yang, Scott Rychnovsky, Ignacia Echeverria and Lan Huang ()
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Clinton Yu: University of California, Irvine
Eric Novitsky: University of California, Irvine
Sree Ganesh Balasubramani: University of California, San Francisco
Xiaorong Wang: University of California, Irvine
Xiyu Shen: University of California, Irvine
Qin Yang: University of California, Irvine
Scott Rychnovsky: University of California, Irvine
Ignacia Echeverria: University of California, San Francisco
Lan Huang: University of California, Irvine

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Cross-linking mass spectrometry (XL-MS) is a powerful technology for mapping protein-protein interactions (PPIs) at the systems level. While bivalent cross-links are effective for defining protein interactions and structures, multivalent cross-links offer enhanced spatial resolution to facilitate characterization of heterogeneous protein complexes. However, their identification remains challenging due to fragmentation complexity and the vast expansion of database search space. Here, we present tris-succinimidyl trioxane (TSTO), a novel trioxane-based, MS-cleavable homotrifunctional cross-linker capable of targeting three proximal lysines simultaneously. TSTO’s unique MS-cleavability enables concurrent release of cross-linked peptide constituents during collision-induced dissociation, permitting their unambiguous identification. The TSTO-based XL-MS platform is effective for mapping cellular networks from intact cells and tissues, illustrating its versatility for complex biological systems. Trimeric interactions captured by TSTO reveal structural details inaccessible to bifunctional reagents, enhancing modeling accuracy and precision. Furthermore, this development opens a new avenue for designing multifunctional MS-cleavable cross-linkers to further advance structural systems biology.

Date: 2025
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DOI: 10.1038/s41467-025-60642-3

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