Phase separation instead of binding strength determines target specificities of MAGUKs

  • Nat Chem Biol. 2025 Jun 10. doi: 10.1038/s41589-025-01925-0.
Yan Chen  #  1  2  3 ,  Chenxue Ma  #  2 ,  Zeyu Shen  1  2 ,  Shiwen Chen  1  2 ,  Shihan Zhu  1  2 ,  Bowen Jia  1  2 ,  Shangyu Dang  2 ,  Mingjie Zhang  4
Affiliations
  • 1. School of Life Sciences, Southern University of Science and Technology, Shenzhen, China.
  • 2. Division of Life Science, Hong Kong University of Science and Technology, Hong Kong, China.
  • 3. Greater Bay Biomedical Innocenter, Shenzhen Bay Laboratory, Shenzhen, China.
  • 4. School of Life Sciences, Southern University of Science and Technology, Shenzhen, China. [email protected].
  • # Contributed equally.
PMID: 40494974 DOI: 10.1038/s41589-025-01925-0
Abstract

Homologous proteins often have distinct functions, even if they share overlapping binding targets. PSD-95 and MAGI-2, two membrane-associated guanylate kinase (MAGUK)-family scaffolds in neuronal synapses, exemplify this. With unknown mechanisms, the two MAGUKs are localized at distinct subsynaptic compartments with PSD-95 inside the postsynaptic density (PSD) and MAGI-2 outside. Here we demonstrate that MAGI-2 forms condensates through phase separation. When coexisting with PSD proteins, the MAGI-2 condensate can enrich the extrasynaptic N-cadherin-β-catenin adhesion complex and the MAGI-2 condensates are immiscible with the PSD-95 condensates. Surprisingly, phosphorylated SAPAP is selectively enriched in the PSD-95 condensate, even though it binds to MAGI-2 with a higher affinity. The specific localization of SAPAP is because of the higher network complexities of the PSD-95-containing condensate than the MAGI-2 condensate. Thus, phase-separation-mediated molecular condensate formation can generate a previously unrecognized mode of molecular interaction and subcellular localization specificities that do not occur in dilute solutions.

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