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Interconnecting Flexibility, Structural Communication, and Function in RhoGEF Oncoproteins

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    Interconnecting Flexibility, Structural Communication, and Function in RhoGEF Oncoproteins
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    • Angelo Felline
      Angelo Felline
      Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy
      More by Angelo Felline
    • Luca Belmonte
      Luca Belmonte
      Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy
      More by Luca Belmonte
      Orcidhttp://orcid.org/0000-0002-7977-9170
    • Francesco Raimondi
      Francesco Raimondi
      Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy
      More by Francesco Raimondi
    • Luca Bellucci
      Luca Bellucci
      Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy
      More by Luca Bellucci
    • Francesca Fanelli*
      Francesca Fanelli
      Department of Life Sciences, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy
      Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, via Campi 287, 41125 Modena, Italy
      *E-mail: [email protected]
      More by Francesca Fanelli
      Orcidhttp://orcid.org/0000-0002-7620-6895
    Other Access OptionsSupporting Information (12)

    Journal of Chemical Information and Modeling

    Cite this: J. Chem. Inf. Model. 2019, 59, 10, 4300–4313
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jcim.9b00271
    Published September 6, 2019
    Copyright © 2019 American Chemical Society
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    Abstract

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    Dbl family Rho guanine nucleotide exchange factors (RhoGEFs) play a central role in cell biology by catalyzing the exchange of guanosine 5′-triphosphate for guanosine 5′-diphosphate (GDP) on RhoA. Insights into the oncogenic constitutive activity of the Lbc RhoGEF were gained by analyzing the structure and dynamics of the protein in different functional states and in comparison with a close homologue, leukemia-associated RhoGEF. Higher intrinsic flexibility, less dense and extended structure network, and less stable allosteric communication pathways in Lbc, compared to the nonconstitutively active homologue, emerged as major determinants of the constitutive activity. Independent of the state, the essential dynamics of the two RhoGEFs is contributed by the last 10 amino acids of Dbl homology (DH) and the whole pleckstrin homology (PH) domains and tends to be equalized by the presence of RhoA. The catalytic activity of the RhoGEF relies on the scaffolding action of the DH domain that primarily turns the switch I (SWI) of RhoA on itself through highly conserved amino acids participating in the stability core and essential for function. Changes in the conformation of SWI and disorganization of the RhoA regions deputed to nucleotide binding are among the major RhoGEF effects leading to GDP release. Binding of RhoA reorganizes the allosteric communication on RhoGEF, strengthening the communication among the canonical RhoA binding site on DH, a secondary RhoA binding site on PH, and the binding site for heterotrimeric G proteins, suggesting dual roles for RhoA as a catalysis substrate and as a regulatory protein. The structure network-based analysis tool employed in this study proved to be useful for predicting potentially druggable regulatory sites in protein structures.

    Copyright © 2019 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jcim.9b00271.

    • Cα-RMSD time series, Cα-RMSD distributions, sequence alignments, comparisons of RhoGEF flexibilities, overall fluctuations of RhoGEFs, stable links at the interdomain and interprotein interfaces, allosteric communication, flexibility and mechanical profiles of RhoA, comparative overall fluctuations of RhoA, distribution of structural hallmarks (Figures S1–S15) (PDF)

    • Cα-RMSD (Table S1) (XLSX)

    • Force constants and amino acid conservation (Table S2) (XLSX)

    • Differences in overall fluctuations (Table S3) (XLSX)

    • Percentage of variance described by the first five PCs (Table S4) (XLSX)

    • Overlaps between the first two PCs (Table S5) (XLSX)

    • Stable hubs in the simulated systems (Table S6) (XLSX)

    • Selected network parameters (Table S7) (XLSX)

    • Community links (Table S8) (XLSX)

    • Nodes involved in stable links at the interface between the DH and PH domains (Table S9) (XLSX)

    • Nodes involved in stable links at the interface between RhoA and Lbc or LARG (Table S10) (XLSX)

    • Linked node pairs participating in the global metapaths (Table S11) (XLSX)

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    This article is cited by 14 publications.

    1. Nurit Haspel, Hyunbum Jang, Ruth Nussinov. Allosteric Activation of RhoA Complexed with p115-RhoGEF Deciphered by Conformational Dynamics. Journal of Chemical Information and Modeling 2024, 64 (3) , 862-873. https://doi.org/10.1021/acs.jcim.3c01412
    2. Sajjad Haider, Mamona Mushtaq, Ali Raza Siddiqui, Sarfaraz Ahmed, Mohammad Nur-e-Alam, Aftab Ahmed, Zaheer Ul-Haq. Unraveling the impact of mutations on the functional dynamics, stability, and energetics of dengue virus non-structural protein 1. Molecular Simulation 2024, 50 (17-18) , 1631-1641. https://doi.org/10.1080/08927022.2024.2421401
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    4. Angelo Felline, Sara Gentile, Francesca Fanelli. psnGPCRdb: The Structure-network Database of G Protein Coupled Receptors. Journal of Molecular Biology 2023, 435 (14) , 167950. https://doi.org/10.1016/j.jmb.2023.167950
    5. Angelo Felline, Simone Conti, Michele Seeber, Marco Cecchini, Francesca Fanelli. Wordom update 2: A user-friendly program for the analysis of molecular structures and conformational ensembles. Computational and Structural Biotechnology Journal 2023, 21 , 1390-1402. https://doi.org/10.1016/j.csbj.2023.01.026
    6. Jian Gu, Xiupeng Zhang, Guiyang Jiang, Qingchang Li, Enhua Wang, Juanhan Yu. ARHGEF40 promotes non‐small cell lung cancer proliferation and invasion via the AKT‐Wnt axis by binding to RhoA. Molecular Carcinogenesis 2022, 61 (11) , 1016-1030. https://doi.org/10.1002/mc.23457
    7. Yanduo Wu, Yongshuang Xiao, Zhizhong Xiao, Yuting Ma, Haixia Zhao, Jun Li. Identification of Male-Specific Molecular Markers by Recombination of RhoGEF10 Gene in Spotted Knifejaw (Oplegnathus punctatus). Genes 2022, 13 (7) , 1262. https://doi.org/10.3390/genes13071262
    8. Marco Cannariato, Marcello Miceli, Marco Cavaglià, Marco A. Deriu. Prediction of Protein–Protein Interactions Between Alsin DH/PH and Rac1 and Resulting Protein Dynamics. Frontiers in Molecular Neuroscience 2022, 14 https://doi.org/10.3389/fnmol.2021.772122
    9. Angelo Felline, Michele Seeber, Francesca Fanelli. PSNtools for standalone and web-based structure network analyses of conformational ensembles. Computational and Structural Biotechnology Journal 2022, 20 , 640-649. https://doi.org/10.1016/j.csbj.2021.12.044
    10. 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 2022, 20 , 5162-5180. https://doi.org/10.1016/j.csbj.2022.09.016
    11. Ennys Gheyouche, Matthias Bagueneau, Gervaise Loirand, Bernard Offmann, Stéphane Téletchéa. Structural Design and Analysis of the RHOA-ARHGEF1 Binding Mode: Challenges and Applications for Protein-Protein Interface Prediction. Frontiers in Molecular Biosciences 2021, 8 https://doi.org/10.3389/fmolb.2021.643728
    12. Angelo Felline, Davide Schiroli, Antonella Comitato, Valeria Marigo, Francesca Fanelli. Structure network-based landscape of rhodopsin misfolding by mutations and algorithmic prediction of small chaperone action. Computational and Structural Biotechnology Journal 2021, 19 , 6020-6038. https://doi.org/10.1016/j.csbj.2021.10.040
    13. Luca Bellucci, Angelo Felline, Francesca Fanelli. Dynamics and structural communication in the ternary complex of fully phosphorylated V2 vasopressin receptor, vasopressin, and β-arrestin 1. Biochimica et Biophysica Acta (BBA) - Biomembranes 2020, 1862 (9) , 183355. https://doi.org/10.1016/j.bbamem.2020.183355
    14. Angelo Felline, Michele Seeber, Francesca Fanelli. webPSN v2.0: a webserver to infer fingerprints of structural communication in biomacromolecules. Nucleic Acids Research 2020, 48 (W1) , W94-W103. https://doi.org/10.1093/nar/gkaa397
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    Journal of Chemical Information and Modeling

    Cite this: J. Chem. Inf. Model. 2019, 59, 10, 4300–4313
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.jcim.9b00271
    Published September 6, 2019
    Copyright © 2019 American Chemical Society
    Request reuse permissions

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