Emergent mechanics of a networked multivalent protein condensate

Zhitao Liao, Bowen Jia, Dongshi Guan (), Xudong Chen, Mingjie Zhang () and Penger Tong ()
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Zhitao Liao: Hong Kong University of Science and Technology, Clear Water Bay
Bowen Jia: Hong Kong University of Science and Technology, Clear Water Bay
Dongshi Guan: Institute of Mechanics, Chinese Academy of Sciences
Xudong Chen: Hong Kong University of Science and Technology, Clear Water Bay
Mingjie Zhang: Hong Kong University of Science and Technology, Clear Water Bay
Penger Tong: Hong Kong University of Science and Technology, Clear Water Bay

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Multivalent proteins can form membraneless condensates in cells by liquid-liquid phase separation, and significant efforts have been made to study their biochemical properties. Here, we demonstrate the emergent mechanics of a functional multivalent condensate reconstituted with six postsynaptic density proteins, using atomic-force-microscopy-based mesoscale rheology and quantitative fluorescence measurements. The measured relaxation modulus and protein mobility reveal that the majority (80%) of the proteins in the condensate are mobile and diffuse through a dynamically cross-linked network made of the remaining (20%) non-mobile scaffold proteins. This percolating structure gives rise to a two-mode mechanical relaxation with an initial exponential decay followed by a long-time power-law decay, which differs significantly from simple Maxwell fluids. The power-law rheology with an exponent α ≃ 0.5 is a hallmark of weak bonds’ binding/unbinding dynamics in the multivalent protein network. The concurrent molecular and mechanical profiling thus provides a reliable readout for characterizing the mechanical state of protein condensates and investigating their physiological functions and associations with diseases.

Date: 2025
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DOI: 10.1038/s41467-025-60345-9

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