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@ARTICLE{Hoffmann:277530,
      author       = {Hoffmann, Christian and Ruff, Kiersten M and Edu, Irina A
                      and Shinn, Min Kyung and Tromm, Johannes V and King, Matthew
                      R and Pant, Avnika and Ausserwöger, Hannes and Morgan,
                      Jennifer R and Knowles, Tuomas P J and Pappu, Rohit V and
                      Milovanovic, Dragomir},
      title        = {{S}ynapsin {C}ondensation is {G}overned by
                      {S}equence-{E}ncoded {M}olecular {G}rammars.},
      journal      = {Journal of molecular biology},
      volume       = {437},
      number       = {8},
      issn         = {0022-2836},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {DZNE-2025-00426},
      pages        = {168987},
      year         = {2025},
      abstract     = {Multiple biomolecular condensates coexist at the pre- and
                      post- synapse to enable vesicle dynamics and controlled
                      neurotransmitter release in the brain. In pre-synapses,
                      intrinsically disordered regions (IDRs) of synaptic proteins
                      are drivers of condensation that enable clustering of
                      synaptic vesicles (SVs). Using computational analysis, we
                      show that the IDRs of SV proteins feature evolutionarily
                      conserved non-random compositional biases and sequence
                      patterns. Synapsin-1 is essential for condensation of SVs,
                      and its C-terminal IDR has been shown to be a key driver of
                      condensation. Focusing on this IDR, we dissected the
                      contributions of two conserved features namely the
                      segregation of polar and proline residues along the linear
                      sequence, and the compositional preference for arginine over
                      lysine. Scrambling the blocks of polar and proline residues
                      weakens the driving forces for forming micron-scale
                      condensates. However, the extent of clustering in
                      subsaturated solutions remains equivalent to that of the
                      wild-type synapsin-1. In contrast, substituting arginine
                      with lysine significantly weakens both the driving forces
                      for condensation and the extent of clustering in
                      subsaturated solutions. Co-expression of the scrambled
                      variant of synapsin-1 with synaptophysin results in a
                      gain-of-function phenotype in cells, whereas arginine to
                      lysine substitutions eliminate condensation in cells. We
                      report an emergent consequence of synapsin-1 condensation,
                      which is the generation of interphase pH gradients that is
                      realized via differential partitioning of protons between
                      coexisting phases. This pH gradient is likely to be directly
                      relevant for vesicular ATPase functions and the loading of
                      neurotransmitters. Our studies highlight how conserved IDR
                      grammars serve as drivers of synapsin-1 condensation.},
      keywords     = {Synapsins: metabolism / Synapsins: chemistry / Synapsins:
                      genetics / Synaptic Vesicles: metabolism / Humans /
                      Intrinsically Disordered Proteins: metabolism /
                      Intrinsically Disordered Proteins: chemistry / Intrinsically
                      Disordered Proteins: genetics / Animals / Amino Acid
                      Sequence / Arginine: metabolism / Arginine: chemistry /
                      Synaptophysin: metabolism / Synaptophysin: genetics /
                      Lysine: metabolism / interphase pH gradient (Other) /
                      microfluidics (Other) / phase separation (Other) / synapse
                      (Other) / synapsin 1 (Other) / Synapsins (NLM Chemicals) /
                      Intrinsically Disordered Proteins (NLM Chemicals) / Arginine
                      (NLM Chemicals) / Synaptophysin (NLM Chemicals) / Lysine
                      (NLM Chemicals)},
      cin          = {AG Milovanovic (Berlin) / AG Milovanovic (Bonn)},
      ddc          = {610},
      cid          = {I:(DE-2719)1813002 / I:(DE-2719)1013043},
      pnm          = {351 - Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39947282},
      doi          = {10.1016/j.jmb.2025.168987},
      url          = {https://pub.dzne.de/record/277530},
}