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Molecular mechanism of GTP binding- and dimerization-induced enhancement of Sar1-mediated membrane remodeling.

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Title: Molecular mechanism of GTP binding- and dimerization-induced enhancement of Sar1-mediated membrane remodeling.
Authors: Paull, Sanjoy1 qiangcui@bu.edu, Audhya, Anjon2, Qiang Cui1,3,4
Source: Proceedings of the National Academy of Sciences of the United States of America. 2/21/2023, Vol. 120 Issue 8, p1-27. 38p.
Subjects: Guanine nucleotide exchange factors, Molecular dynamics, N-terminal residues, Membrane transport proteins, Biological transport
Abstract: The Sar1 GTPase initiates coat protein II (COPII)-mediated protein transport by generating membrane curvature at subdomains on the endoplasmic reticulum, where it is activated by the guanine nucleotide exchange factor (GEF) Sec12. Crystal structures of GDP- and GTP-bound forms of Sar1 suggest that it undergoes a conformational switch in whichGTPbinding enhances the exposure of an amino-terminal amphipathic helix necessary for efficient membrane penetration. However, key residues in the amino terminus were not resolved in crystal structures, and experimental studies have suggested that the amino terminus of Sar1 is solvent-exposed in the absence of a membrane, even in the GDP-bound state. Therefore, the molecular mechanism by which GTP binding activates the membrane-remodeling activity of Sar1 remains unclear. Using atomistic molecular dynamics simulations, we compare the membranebinding and curvature generation activities of Sar1 in its GDP- and GTP-bound states. We show that in the GTP-bound state, Sar1 inserts into the membrane with its complete (residues 1 to 23) amphipathic amino-terminal helix, while Sar1-GDP binds to the membrane only through its first 12 residues. Such differential membranebinding modes translate into significant differences in the protein volume inserted into the membrane. As a result, Sar1-GTP generates positive membrane curvature 10 to 20 times higher than Sar1-GDP. Dimerization of the GTP-bound form of Sar1 further amplifies curvature generation. Taken together, our results present a detailed molecular mechanism for how the nucleotide-bound state of Sar1 regulates its membrane-binding and remodeling activities in a concentration-dependent manner, paving the way toward a better understanding COPII-mediated membrane transport. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Molecular mechanism of GTP binding- and dimerization-induced enhancement of Sar1-mediated membrane remodeling.
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  Data: <searchLink fieldCode="AR" term="%22Paull%2C+Sanjoy%22">Paull, Sanjoy</searchLink><relatesTo>1</relatesTo><i> qiangcui@bu.edu</i><br /><searchLink fieldCode="AR" term="%22Audhya%2C+Anjon%22">Audhya, Anjon</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Qiang+Cui%22">Qiang Cui</searchLink><relatesTo>1,3,4</relatesTo>
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  Data: <searchLink fieldCode="DE" term="%22Guanine+nucleotide+exchange+factors%22">Guanine nucleotide exchange factors</searchLink><br /><searchLink fieldCode="DE" term="%22Molecular+dynamics%22">Molecular dynamics</searchLink><br /><searchLink fieldCode="DE" term="%22N-terminal+residues%22">N-terminal residues</searchLink><br /><searchLink fieldCode="DE" term="%22Membrane+transport+proteins%22">Membrane transport proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Biological+transport%22">Biological transport</searchLink>
– Name: Abstract
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  Data: The Sar1 GTPase initiates coat protein II (COPII)-mediated protein transport by generating membrane curvature at subdomains on the endoplasmic reticulum, where it is activated by the guanine nucleotide exchange factor (GEF) Sec12. Crystal structures of GDP- and GTP-bound forms of Sar1 suggest that it undergoes a conformational switch in whichGTPbinding enhances the exposure of an amino-terminal amphipathic helix necessary for efficient membrane penetration. However, key residues in the amino terminus were not resolved in crystal structures, and experimental studies have suggested that the amino terminus of Sar1 is solvent-exposed in the absence of a membrane, even in the GDP-bound state. Therefore, the molecular mechanism by which GTP binding activates the membrane-remodeling activity of Sar1 remains unclear. Using atomistic molecular dynamics simulations, we compare the membranebinding and curvature generation activities of Sar1 in its GDP- and GTP-bound states. We show that in the GTP-bound state, Sar1 inserts into the membrane with its complete (residues 1 to 23) amphipathic amino-terminal helix, while Sar1-GDP binds to the membrane only through its first 12 residues. Such differential membranebinding modes translate into significant differences in the protein volume inserted into the membrane. As a result, Sar1-GTP generates positive membrane curvature 10 to 20 times higher than Sar1-GDP. Dimerization of the GTP-bound form of Sar1 further amplifies curvature generation. Taken together, our results present a detailed molecular mechanism for how the nucleotide-bound state of Sar1 regulates its membrane-binding and remodeling activities in a concentration-dependent manner, paving the way toward a better understanding COPII-mediated membrane transport. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
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  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1073/pnas.2212513120
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        Text: English
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        PageCount: 38
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      – SubjectFull: Guanine nucleotide exchange factors
        Type: general
      – SubjectFull: Molecular dynamics
        Type: general
      – SubjectFull: N-terminal residues
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      – SubjectFull: Membrane transport proteins
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      – SubjectFull: Biological transport
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      – TitleFull: Molecular mechanism of GTP binding- and dimerization-induced enhancement of Sar1-mediated membrane remodeling.
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            NameFull: Paull, Sanjoy
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              Text: 2/21/2023
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              Y: 2023
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