Structural communication between the GTPase Sec4p and its activator Sec2p: Determinants of GEF activity and early deformations to nucleotide release
Ras GTPases are molecular switches that cycle between OFF and ON states depending on the bound nucleotide (i.e. GDP-bound and GTP-bound, respectively).The Rab GTPase, Sec4p, plays regulatory roles in multiple steps of intracellular vesicle trafficking. Nucleotide release is catalyzed by the Guanine...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Computational and Structural Biotechnology Journal |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037022004214 |
| _version_ | 1797978179505225728 |
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| author | Angelo Felline Francesco Raimondi Sara Gentile Francesca Fanelli |
| author_facet | Angelo Felline Francesco Raimondi Sara Gentile Francesca Fanelli |
| author_sort | Angelo Felline |
| collection | DOAJ |
| description | Ras GTPases are molecular switches that cycle between OFF and ON states depending on the bound nucleotide (i.e. GDP-bound and GTP-bound, respectively).The Rab GTPase, Sec4p, plays regulatory roles in multiple steps of intracellular vesicle trafficking. Nucleotide release is catalyzed by the Guanine Nucleotide Exchange Factor (GEF) Sec2p.Here, the integration of structural information with molecular dynamics (MD) simulations addressed a number of questions concerning the intrinsic and stimulated dynamics of Sec2p and Sec4p as well as the chain of structural deformations leading to GEF-assisted activation of the Rab GTPase.Sec2p holds an intrinsic ability to adopt the conformation found in the crystallographic complexes with Sec4p, thus suggesting that the latter selects and shifts the conformational equilibrium towards a pre-existing bound-like conformation of Sec2p.The anchoring of Sec4p to a suitable conformation of Sec2p favors the Sec2p-assisted pulling on itself of the α1/switch 1 (SWI) loop and of SWI, which loose any contact with GDP. Those deformations of Sec4p would occur earlier. Formation of the final Sec2p-Sec4p hydrophobic interface, accomplishes later. Disruption of the nucleotide cage would cause firstly loss of interactions with the guanine ring and secondly loss of interactions with the phosphates.The ease in sampling the energy landscape and adopting a bound-like conformation likely favors the catalyzing ability of GEFs for Ras GTPases. |
| first_indexed | 2024-04-11T05:18:52Z |
| format | Article |
| id | doaj.art-cc80bd3d646340f5beb04e2fc1d9c6c2 |
| institution | Directory Open Access Journal |
| issn | 2001-0370 |
| language | English |
| last_indexed | 2024-04-11T05:18:52Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Computational and Structural Biotechnology Journal |
| spelling | doaj.art-cc80bd3d646340f5beb04e2fc1d9c6c22022-12-24T04:54:27ZengElsevierComputational and Structural Biotechnology Journal2001-03702022-01-012051625180Structural communication between the GTPase Sec4p and its activator Sec2p: Determinants of GEF activity and early deformations to nucleotide releaseAngelo Felline0Francesco Raimondi1Sara Gentile2Francesca Fanelli3Department of Life Sciences, University of Modena and Reggio Emilia, via Campy 103, 41125 Modena, ItalyDepartment of Life Sciences, University of Modena and Reggio Emilia, via Campy 103, 41125 Modena, Italy; Scuola Normale Superiore Pisa, Piazza dei Cavalieri, 7 – 56126 Pisa, ItalyDepartment of Life Sciences, University of Modena and Reggio Emilia, via Campy 103, 41125 Modena, ItalyDepartment of Life Sciences, University of Modena and Reggio Emilia, via Campy 103, 41125 Modena, Italy; Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, via Campi 287, 41125 Modena, Italy; Corresponding author at: Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena.Ras GTPases are molecular switches that cycle between OFF and ON states depending on the bound nucleotide (i.e. GDP-bound and GTP-bound, respectively).The Rab GTPase, Sec4p, plays regulatory roles in multiple steps of intracellular vesicle trafficking. Nucleotide release is catalyzed by the Guanine Nucleotide Exchange Factor (GEF) Sec2p.Here, the integration of structural information with molecular dynamics (MD) simulations addressed a number of questions concerning the intrinsic and stimulated dynamics of Sec2p and Sec4p as well as the chain of structural deformations leading to GEF-assisted activation of the Rab GTPase.Sec2p holds an intrinsic ability to adopt the conformation found in the crystallographic complexes with Sec4p, thus suggesting that the latter selects and shifts the conformational equilibrium towards a pre-existing bound-like conformation of Sec2p.The anchoring of Sec4p to a suitable conformation of Sec2p favors the Sec2p-assisted pulling on itself of the α1/switch 1 (SWI) loop and of SWI, which loose any contact with GDP. Those deformations of Sec4p would occur earlier. Formation of the final Sec2p-Sec4p hydrophobic interface, accomplishes later. Disruption of the nucleotide cage would cause firstly loss of interactions with the guanine ring and secondly loss of interactions with the phosphates.The ease in sampling the energy landscape and adopting a bound-like conformation likely favors the catalyzing ability of GEFs for Ras GTPases.http://www.sciencedirect.com/science/article/pii/S2001037022004214Molecular dynamics simulationsProtein–protein dockingRas GTPasesGuanine nucleotide exchange factorProtein structure networkStructural communication |
| spellingShingle | Angelo Felline Francesco Raimondi Sara Gentile Francesca Fanelli Structural communication between the GTPase Sec4p and its activator Sec2p: Determinants of GEF activity and early deformations to nucleotide release Computational and Structural Biotechnology Journal Molecular dynamics simulations Protein–protein docking Ras GTPases Guanine nucleotide exchange factor Protein structure network Structural communication |
| title | Structural communication between the GTPase Sec4p and its activator Sec2p: Determinants of GEF activity and early deformations to nucleotide release |
| title_full | Structural communication between the GTPase Sec4p and its activator Sec2p: Determinants of GEF activity and early deformations to nucleotide release |
| title_fullStr | Structural communication between the GTPase Sec4p and its activator Sec2p: Determinants of GEF activity and early deformations to nucleotide release |
| title_full_unstemmed | Structural communication between the GTPase Sec4p and its activator Sec2p: Determinants of GEF activity and early deformations to nucleotide release |
| title_short | Structural communication between the GTPase Sec4p and its activator Sec2p: Determinants of GEF activity and early deformations to nucleotide release |
| title_sort | structural communication between the gtpase sec4p and its activator sec2p determinants of gef activity and early deformations to nucleotide release |
| topic | Molecular dynamics simulations Protein–protein docking Ras GTPases Guanine nucleotide exchange factor Protein structure network Structural communication |
| url | http://www.sciencedirect.com/science/article/pii/S2001037022004214 |
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