277530 20260310111155.0 pmc:PMC11903162 pmc 10.1016/j.jmb.2025.168987 doi pmid:39947282 pmid 0022-2836 ISSN 1089-8638 ISSN DZNE-2025-00426 English 610 Hoffmann, Christian P:(DE-2719)9000582 0 First author dzne Synapsin Condensation is Governed by Sequence-Encoded Molecular Grammars. Amsterdam [u.a.] 2025 Elsevier article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1742380238_22981 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote 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. 351 - Brain Function (POF4-351) G:(DE-HGF)POF4-351 POF4-351 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de interphase pH gradient Other microfluidics Other phase separation Other synapse Other synapsin 1 Other Synapsins NLM Chemicals Intrinsically Disordered Proteins NLM Chemicals Arginine 94ZLA3W45F NLM Chemicals Synaptophysin NLM Chemicals Lysine K3Z4F929H6 NLM Chemicals Synapsins: metabolism MeSH Synapsins: chemistry MeSH Synapsins: genetics MeSH Synaptic Vesicles: metabolism MeSH Humans MeSH Intrinsically Disordered Proteins: metabolism MeSH Intrinsically Disordered Proteins: chemistry MeSH Intrinsically Disordered Proteins: genetics MeSH Animals MeSH Amino Acid Sequence MeSH Arginine: metabolism MeSH Arginine: chemistry MeSH Synaptophysin: metabolism MeSH Synaptophysin: genetics MeSH Lysine: metabolism MeSH Ruff, Kiersten M 1 Edu, Irina A 2 Shinn, Min Kyung 3 Tromm, Johannes V P:(DE-2719)9002092 4 dzne King, Matthew R 5 Pant, Avnika 6 Ausserwöger, Hannes 7 Morgan, Jennifer R 8 Knowles, Tuomas P J 9 Pappu, Rohit V 10 Milovanovic, Dragomir P:(DE-2719)9000670 11 Last author dzne 10.1016/j.jmb.2025.168987 Vol. 437, no. 8, p. 168987 - PERI:(DE-600)1355192-9 8 168987 Journal of molecular biology 437 2025 0022-2836 http://pub.dzne.de/record/277530/files/DZNE-2025-00426%20SUP.docx OpenAccess http://pub.dzne.de/record/277530/files/DZNE-2025-00426.pdf http://pub.dzne.de/record/277530/files/DZNE-2025-00426%20SUP.doc http://pub.dzne.de/record/277530/files/DZNE-2025-00426%20SUP.odt http://pub.dzne.de/record/277530/files/DZNE-2025-00426%20SUP.pdf OpenAccess pdfa http://pub.dzne.de/record/277530/files/DZNE-2025-00426.pdf?subformat=pdfa #685 2575 Hybrid-OA 2026-03-09 DEAL oai:pub.dzne.de:277530 openaire open_access OpenAPC_DEAL driver VDB openCost dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 0 P:(DE-2719)9000582 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 4 P:(DE-2719)9002092 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 11 P:(DE-2719)9000670 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-351 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Brain Function 0 2025 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2024-12-13 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2024-12-13 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2024-12-13 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2024-12-13 DBCoverage StatID:(DE-HGF)0600 StatID Ebsco Academic Search 2024-12-13 Creative Commons Attribution-NonCommercial-NoDerivs CC BY-NC-ND 4.0 LIC:(DE-HGF)CCBYNCND4 HGFVOC JCR StatID:(DE-HGF)0100 StatID J MOL BIOL : 2022 2024-12-13 DBCoverage StatID:(DE-HGF)1030 StatID Current Contents - Life Sciences 2024-12-13 WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2024-12-13 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2024-12-13 OpenAccess StatID:(DE-HGF)0510 StatID Peer Review StatID:(DE-HGF)0030 StatID ASC 2024-12-13 IF >= 5 StatID:(DE-HGF)9905 StatID J MOL BIOL : 2022 2024-12-13 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2024-12-13 Nationallizenz StatID:(DE-HGF)0420 StatID 2024-12-13 ger DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2024-12-13 APC keys set APC PC:(DE-HGF)0000 Local Funding APC PC:(DE-HGF)0001 I:(DE-2719)1813002 AG Milovanovic (Berlin) Molecular Neuroscience 0 I:(DE-2719)1013043 AG Milovanovic (Bonn) Molecular Neuroscience 1 FullTexts journal VDB UNRESTRICTED I:(DE-2719)1813002 I:(DE-2719)1013043 APC