Effect of Ser392 Phosphorylation on the Structure and Dynamics of the Polybasic Domain of ADP Ribosylation Factor Nucleotide Site Opener Protein: A Molecular Simulation Study
ADP ribosylation factor nucleotide site opener (ARNO) as a guanine nucleotide exchange factor (GEF) activates small GTPases called ADP ribosylation factors (Arfs), which function as molecular switches and regulate a variety of cell biological events. ARNO directly interacts with the transmembrane a2...
| Main Authors: | , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
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2016
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| Online Access: | https://hdl.handle.net/10356/82008 http://hdl.handle.net/10220/41058 |
| _version_ | 1826122716916219904 |
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| author | Srinivasaraghavan, Kannan Nacro, Kassoum Grüber, Gerhard Verma, Chandra Shekhar |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Srinivasaraghavan, Kannan Nacro, Kassoum Grüber, Gerhard Verma, Chandra Shekhar |
| author_sort | Srinivasaraghavan, Kannan |
| collection | NTU |
| description | ADP ribosylation factor nucleotide site opener (ARNO) as a guanine nucleotide exchange factor (GEF) activates small GTPases called ADP ribosylation factors (Arfs), which function as molecular switches and regulate a variety of cell biological events. ARNO directly interacts with the transmembrane a2-subunit isoform of the proton-pumping vacuolar ATPase in an acidification-dependent manner, and this interaction plays a crucial role in the regulation of the protein degradation pathway. A recent study reported specific interactions of a2N with the ARNO375–400 peptide corresponding to the polybasic (PB) domain of ARNO, which is a crucial regulatory element in the autoregulation and modulation of Arf-GEF activity. Interestingly, phosphorylation of Ser392 completely abolishes this interaction, and the experimental structure shows significant structural rearrangements. To investigate the effect of Ser392 phosphorylation on the structure and dynamics of the ARNO375–400 peptide, we employed all atom molecular dynamics (MD) simulations of the phosphorylated and unphosphorylated PB domain of the ARNO protein. A Hamiltonian-based replica exchange method called biasing potential replica exchange MD was used to enhance conformational sampling. Simulations predicted that the isolated PB domain is highly flexible, with the C-terminal region of the unphosphorylated state being unstable. In contrast, Ser392 phosphorylation increases the overall stability of the peptide. In agreement with experimental results, our simulations further support the hypothesis that phosphorylation induces disorder to order transitions and provide new insights into the structural dynamics of the PB domain. Phosphorylation of Ser392 appears to stabilize the C-terminal α-helix via formation of salt bridges between phospho-Ser392 and Arg390, Lys395, and Lys396. |
| first_indexed | 2024-10-01T05:53:04Z |
| format | Journal Article |
| id | ntu-10356/82008 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:53:04Z |
| publishDate | 2016 |
| record_format | dspace |
| spelling | ntu-10356/820082020-03-07T12:18:09Z Effect of Ser392 Phosphorylation on the Structure and Dynamics of the Polybasic Domain of ADP Ribosylation Factor Nucleotide Site Opener Protein: A Molecular Simulation Study Srinivasaraghavan, Kannan Nacro, Kassoum Grüber, Gerhard Verma, Chandra Shekhar School of Biological Sciences Conformational samplings Adp-ribosylation factors ADP ribosylation factor nucleotide site opener (ARNO) as a guanine nucleotide exchange factor (GEF) activates small GTPases called ADP ribosylation factors (Arfs), which function as molecular switches and regulate a variety of cell biological events. ARNO directly interacts with the transmembrane a2-subunit isoform of the proton-pumping vacuolar ATPase in an acidification-dependent manner, and this interaction plays a crucial role in the regulation of the protein degradation pathway. A recent study reported specific interactions of a2N with the ARNO375–400 peptide corresponding to the polybasic (PB) domain of ARNO, which is a crucial regulatory element in the autoregulation and modulation of Arf-GEF activity. Interestingly, phosphorylation of Ser392 completely abolishes this interaction, and the experimental structure shows significant structural rearrangements. To investigate the effect of Ser392 phosphorylation on the structure and dynamics of the ARNO375–400 peptide, we employed all atom molecular dynamics (MD) simulations of the phosphorylated and unphosphorylated PB domain of the ARNO protein. A Hamiltonian-based replica exchange method called biasing potential replica exchange MD was used to enhance conformational sampling. Simulations predicted that the isolated PB domain is highly flexible, with the C-terminal region of the unphosphorylated state being unstable. In contrast, Ser392 phosphorylation increases the overall stability of the peptide. In agreement with experimental results, our simulations further support the hypothesis that phosphorylation induces disorder to order transitions and provide new insights into the structural dynamics of the PB domain. Phosphorylation of Ser392 appears to stabilize the C-terminal α-helix via formation of salt bridges between phospho-Ser392 and Arg390, Lys395, and Lys396. ASTAR (Agency for Sci., Tech. and Research, S’pore) 2016-08-03T09:24:29Z 2019-12-06T14:44:36Z 2016-08-03T09:24:29Z 2019-12-06T14:44:36Z 2013 Journal Article Srinivasaraghavan, K., Nacro, K., Grüber, G., & Verma, C. S. (2013). Effect of Ser392 Phosphorylation on the Structure and Dynamics of the Polybasic Domain of ADP Ribosylation Factor Nucleotide Site Opener Protein: A Molecular Simulation Study. Biochemistry, 52(41), 7339-7349. https://hdl.handle.net/10356/82008 http://hdl.handle.net/10220/41058 10.1021/bi400912e en Biochemistry © 2013 American Chemical Society. 11 p. |
| spellingShingle | Conformational samplings Adp-ribosylation factors Srinivasaraghavan, Kannan Nacro, Kassoum Grüber, Gerhard Verma, Chandra Shekhar Effect of Ser392 Phosphorylation on the Structure and Dynamics of the Polybasic Domain of ADP Ribosylation Factor Nucleotide Site Opener Protein: A Molecular Simulation Study |
| title | Effect of Ser392 Phosphorylation on the Structure and Dynamics of the Polybasic Domain of ADP Ribosylation Factor Nucleotide Site Opener Protein: A Molecular Simulation Study |
| title_full | Effect of Ser392 Phosphorylation on the Structure and Dynamics of the Polybasic Domain of ADP Ribosylation Factor Nucleotide Site Opener Protein: A Molecular Simulation Study |
| title_fullStr | Effect of Ser392 Phosphorylation on the Structure and Dynamics of the Polybasic Domain of ADP Ribosylation Factor Nucleotide Site Opener Protein: A Molecular Simulation Study |
| title_full_unstemmed | Effect of Ser392 Phosphorylation on the Structure and Dynamics of the Polybasic Domain of ADP Ribosylation Factor Nucleotide Site Opener Protein: A Molecular Simulation Study |
| title_short | Effect of Ser392 Phosphorylation on the Structure and Dynamics of the Polybasic Domain of ADP Ribosylation Factor Nucleotide Site Opener Protein: A Molecular Simulation Study |
| title_sort | effect of ser392 phosphorylation on the structure and dynamics of the polybasic domain of adp ribosylation factor nucleotide site opener protein a molecular simulation study |
| topic | Conformational samplings Adp-ribosylation factors |
| url | https://hdl.handle.net/10356/82008 http://hdl.handle.net/10220/41058 |
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