Driving forces for condensation of synapsin are governed by sequence-encoded molecular grammars DOI Creative Commons
Christian Pieter Hoffmann, Kiersten M. Ruff, Irina A. Edu

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 4, 2024

Multiple biomolecular condensates coexist at the pre- and post- synapse to enable vesicle dynamics controlled neurotransmitter release in brain. In pre-synapses, intrinsically disordered regions (IDRs) of synaptic proteins are drivers condensation that clustering vesicles (SVs). Using computational analysis, we show IDRs SV feature evolutionarily conserved non-random compositional biases sequence patterns. Synapsin-1 is essential for SVs, its C-terminal IDR has been shown be a key driver condensation. Focusing on this IDR, dissected contributions two features namely segregation polar proline residues along linear sequence, preference arginine over lysine. Scrambling blocks weakens driving forces forming micron-scale condensates. However, extent subsaturated solutions remains equivalent wild-type synapsin-1. contrast, substituting with lysine significantly both solutions. Co-expression scrambled variant synapsin-1 synaptophysin results gain-of-function phenotype cells, whereas substitutions eliminate We report an emergent consequence condensation, which generation interphase pH gradients realized via differential partitioning protons between coexisting phases. This gradient likely directly relevant vesicular ATPase functions loading neurotransmitters. Our study highlights how grammars serve as

Language: Английский

Live-cell quantification reveals viscoelastic regulation of synapsin condensates by α-synuclein DOI Creative Commons
Huan Wang, Christian Hoffmann, Johannes Vincent Tromm

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(16)

Published: April 18, 2025

Synapsin and α-synuclein represent a growing list of condensate-forming proteins where the material states condensates are directly linked to cellular functions (e.g., neurotransmission) pathology neurodegeneration). However, quantifying condensate properties in living systems has been substantial challenge. Here, we develop micropipette aspiration whole-cell patch-clamp (MAPAC), platform that allows direct quantification live cells. We find 10,000-fold variations viscoelasticity synapsin condensates, regulated by partitioning α-synuclein, marker for synucleinopathies. Through vitro reconstitutions, identify multiple molecular factors distinctly regulate viscosity, interfacial tension, maturation confirming roles α-synuclein. Overall, our study provides unprecedented quantitative insights into neuronal reveals crucial role regulating viscoelasticity. Furthermore, envision MAPAC applicable broad range vivo.

Language: Английский

Citations

1
Synapsin condensation is governed by sequence-encoded molecular grammars DOI Creative Commons
Christian Pieter Hoffmann, Kiersten M. Ruff, Irina A. Edu

et al.

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 168987 - 168987

Published: Feb. 1, 2025

Multiple biomolecular condensates coexist at the pre- and post- synapse to enable vesicle dynamics controlled neurotransmitter release in brain. In pre-synapses, intrinsically disordered regions (IDRs) of synaptic proteins are drivers condensation that clustering vesicles (SVs). Using computational analysis, we show IDRs SV feature evolutionarily conserved non-random compositional biases sequence patterns. Synapsin-1 is essential for SVs, its C-terminal IDR has been shown be a key driver condensation. Focusing on this IDR, dissected contributions two features namely segregation polar proline residues along linear sequence, preference arginine over lysine. Scrambling blocks weakens driving forces forming micron-scale condensates. However, extent subsaturated solutions remains equivalent wild-type synapsin-1. contrast, substituting with lysine significantly both solutions. Co-expression scrambled variant synapsin-1 synaptophysin results gain-of-function phenotype cells, whereas substitutions eliminate cells. We report an emergent consequence condensation, which generation interphase pH gradients realized via differential partitioning protons between coexisting phases. This gradient likely directly relevant vesicular ATPase functions loading neurotransmitters. Our studies highlight how grammars serve as

Language: Английский

Citations

0
Driving forces for condensation of synapsin are governed by sequence-encoded molecular grammars DOI Creative Commons
Christian Pieter Hoffmann, Kiersten M. Ruff, Irina A. Edu

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 4, 2024

Multiple biomolecular condensates coexist at the pre- and post- synapse to enable vesicle dynamics controlled neurotransmitter release in brain. In pre-synapses, intrinsically disordered regions (IDRs) of synaptic proteins are drivers condensation that clustering vesicles (SVs). Using computational analysis, we show IDRs SV feature evolutionarily conserved non-random compositional biases sequence patterns. Synapsin-1 is essential for SVs, its C-terminal IDR has been shown be a key driver condensation. Focusing on this IDR, dissected contributions two features namely segregation polar proline residues along linear sequence, preference arginine over lysine. Scrambling blocks weakens driving forces forming micron-scale condensates. However, extent subsaturated solutions remains equivalent wild-type synapsin-1. contrast, substituting with lysine significantly both solutions. Co-expression scrambled variant synapsin-1 synaptophysin results gain-of-function phenotype cells, whereas substitutions eliminate We report an emergent consequence condensation, which generation interphase pH gradients realized via differential partitioning protons between coexisting phases. This gradient likely directly relevant vesicular ATPase functions loading neurotransmitters. Our study highlights how grammars serve as

Language: Английский

Citations

2