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000277530 1001_ $$0P:(DE-2719)9000582$$aHoffmann, Christian$$b0$$eFirst author$$udzne
000277530 245__ $$aSynapsin Condensation is Governed by Sequence-Encoded Molecular Grammars.
000277530 260__ $$aAmsterdam [u.a.]$$bElsevier$$c2025
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000277530 520__ $$aMultiple 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.
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000277530 650_7 $$2Other$$ainterphase pH gradient
000277530 650_7 $$2Other$$amicrofluidics
000277530 650_7 $$2Other$$aphase separation
000277530 650_7 $$2Other$$asynapse
000277530 650_7 $$2Other$$asynapsin 1
000277530 650_7 $$2NLM Chemicals$$aSynapsins
000277530 650_7 $$2NLM Chemicals$$aIntrinsically Disordered Proteins
000277530 650_7 $$094ZLA3W45F$$2NLM Chemicals$$aArginine
000277530 650_7 $$2NLM Chemicals$$aSynaptophysin
000277530 650_7 $$0K3Z4F929H6$$2NLM Chemicals$$aLysine
000277530 650_2 $$2MeSH$$aSynapsins: metabolism
000277530 650_2 $$2MeSH$$aSynapsins: chemistry
000277530 650_2 $$2MeSH$$aSynapsins: genetics
000277530 650_2 $$2MeSH$$aSynaptic Vesicles: metabolism
000277530 650_2 $$2MeSH$$aHumans
000277530 650_2 $$2MeSH$$aIntrinsically Disordered Proteins: metabolism
000277530 650_2 $$2MeSH$$aIntrinsically Disordered Proteins: chemistry
000277530 650_2 $$2MeSH$$aIntrinsically Disordered Proteins: genetics
000277530 650_2 $$2MeSH$$aAnimals
000277530 650_2 $$2MeSH$$aAmino Acid Sequence
000277530 650_2 $$2MeSH$$aArginine: metabolism
000277530 650_2 $$2MeSH$$aArginine: chemistry
000277530 650_2 $$2MeSH$$aSynaptophysin: metabolism
000277530 650_2 $$2MeSH$$aSynaptophysin: genetics
000277530 650_2 $$2MeSH$$aLysine: metabolism
000277530 7001_ $$aRuff, Kiersten M$$b1
000277530 7001_ $$aEdu, Irina A$$b2
000277530 7001_ $$aShinn, Min Kyung$$b3
000277530 7001_ $$0P:(DE-2719)9002092$$aTromm, Johannes V$$b4$$udzne
000277530 7001_ $$aKing, Matthew R$$b5
000277530 7001_ $$aPant, Avnika$$b6
000277530 7001_ $$aAusserwöger, Hannes$$b7
000277530 7001_ $$aMorgan, Jennifer R$$b8
000277530 7001_ $$aKnowles, Tuomas P J$$b9
000277530 7001_ $$aPappu, Rohit V$$b10
000277530 7001_ $$0P:(DE-2719)9000670$$aMilovanovic, Dragomir$$b11$$eLast author$$udzne
000277530 773__ $$0PERI:(DE-600)1355192-9$$a10.1016/j.jmb.2025.168987$$gVol. 437, no. 8, p. 168987 -$$n8$$p168987$$tJournal of molecular biology$$v437$$x0022-2836$$y2025
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