The Role of Membrane Affinity and Binding Modes in Alpha-Synuclein Regulation of Vesicle Release and Trafficking
Alpha-synuclein is a presynaptic protein linked to Parkinson’s disease with a poorly characterized physiological role in regulating the synaptic vesicle cycle. Using RBL-2H3 cells as a model system, we earlier reported that wild-type alpha-synuclein can act as both an inhibitor and a potentiator of...
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| Format: | Article |
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MDPI AG
2022-12-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/12/1816 |
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| author | Tapojyoti Das Meraj Ramezani David Snead Cristian Follmer Peter Chung Ka Yee Lee David A. Holowka Barbara A. Baird David Eliezer |
| author_facet | Tapojyoti Das Meraj Ramezani David Snead Cristian Follmer Peter Chung Ka Yee Lee David A. Holowka Barbara A. Baird David Eliezer |
| author_sort | Tapojyoti Das |
| collection | DOAJ |
| description | Alpha-synuclein is a presynaptic protein linked to Parkinson’s disease with a poorly characterized physiological role in regulating the synaptic vesicle cycle. Using RBL-2H3 cells as a model system, we earlier reported that wild-type alpha-synuclein can act as both an inhibitor and a potentiator of stimulated exocytosis in a concentration-dependent manner. The inhibitory function is constitutive and depends on membrane binding by the helix-2 region of the lipid-binding domain, while potentiation becomes apparent only at high concentrations. Using structural and functional characterization of conformationally selective mutants via a combination of spectroscopic and cellular assays, we show here that binding affinity for isolated vesicles similar in size to synaptic vesicles is a primary determinant of alpha-synuclein-mediated potentiation of vesicle release. Inhibition of release is sensitive to changes in the region linking the helix-1 and helix-2 regions of the N-terminal lipid-binding domain and may require some degree of coupling between these regions. Potentiation of release likely occurs as a result of alpha-synuclein interactions with undocked vesicles isolated away from the active zone in internal pools. Consistent with this, we observe that alpha-synuclein can disperse vesicles from in vitro clusters organized by condensates of the presynaptic protein synapsin-1. |
| first_indexed | 2024-03-09T17:17:46Z |
| format | Article |
| id | doaj.art-f60c6c30da694b5eb9dac1e470eda639 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T17:17:46Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-f60c6c30da694b5eb9dac1e470eda6392023-11-24T13:33:50ZengMDPI AGBiomolecules2218-273X2022-12-011212181610.3390/biom12121816The Role of Membrane Affinity and Binding Modes in Alpha-Synuclein Regulation of Vesicle Release and TraffickingTapojyoti Das0Meraj Ramezani1David Snead2Cristian Follmer3Peter Chung4Ka Yee Lee5David A. Holowka6Barbara A. Baird7David Eliezer8Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USADepartment of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USADepartment of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USALaboratory of Biological Chemistry of Neurodegenerative Disorders, Department of Physical-Chemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro 22290-240, BrazilDepartment of Chemistry, James Franck Institute, Institute of Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USADepartment of Chemistry, James Franck Institute, Institute of Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USADepartment of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USADepartment of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USADepartment of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USAAlpha-synuclein is a presynaptic protein linked to Parkinson’s disease with a poorly characterized physiological role in regulating the synaptic vesicle cycle. Using RBL-2H3 cells as a model system, we earlier reported that wild-type alpha-synuclein can act as both an inhibitor and a potentiator of stimulated exocytosis in a concentration-dependent manner. The inhibitory function is constitutive and depends on membrane binding by the helix-2 region of the lipid-binding domain, while potentiation becomes apparent only at high concentrations. Using structural and functional characterization of conformationally selective mutants via a combination of spectroscopic and cellular assays, we show here that binding affinity for isolated vesicles similar in size to synaptic vesicles is a primary determinant of alpha-synuclein-mediated potentiation of vesicle release. Inhibition of release is sensitive to changes in the region linking the helix-1 and helix-2 regions of the N-terminal lipid-binding domain and may require some degree of coupling between these regions. Potentiation of release likely occurs as a result of alpha-synuclein interactions with undocked vesicles isolated away from the active zone in internal pools. Consistent with this, we observe that alpha-synuclein can disperse vesicles from in vitro clusters organized by condensates of the presynaptic protein synapsin-1.https://www.mdpi.com/2218-273X/12/12/1816alpha-synucleinmembranesynaptic vesiclesynapsinParkinson’s |
| spellingShingle | Tapojyoti Das Meraj Ramezani David Snead Cristian Follmer Peter Chung Ka Yee Lee David A. Holowka Barbara A. Baird David Eliezer The Role of Membrane Affinity and Binding Modes in Alpha-Synuclein Regulation of Vesicle Release and Trafficking Biomolecules alpha-synuclein membrane synaptic vesicle synapsin Parkinson’s |
| title | The Role of Membrane Affinity and Binding Modes in Alpha-Synuclein Regulation of Vesicle Release and Trafficking |
| title_full | The Role of Membrane Affinity and Binding Modes in Alpha-Synuclein Regulation of Vesicle Release and Trafficking |
| title_fullStr | The Role of Membrane Affinity and Binding Modes in Alpha-Synuclein Regulation of Vesicle Release and Trafficking |
| title_full_unstemmed | The Role of Membrane Affinity and Binding Modes in Alpha-Synuclein Regulation of Vesicle Release and Trafficking |
| title_short | The Role of Membrane Affinity and Binding Modes in Alpha-Synuclein Regulation of Vesicle Release and Trafficking |
| title_sort | role of membrane affinity and binding modes in alpha synuclein regulation of vesicle release and trafficking |
| topic | alpha-synuclein membrane synaptic vesicle synapsin Parkinson’s |
| url | https://www.mdpi.com/2218-273X/12/12/1816 |
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