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New structural insights into the role of TROVE2 complexes in the on-set and pathogenesis of systemic lupus erythematosus determined by a combination of QCM-D and DPI

  • Augusto Juste-Dolz
  • Noelle M. do Nascimento
  • Isidro Monzó
  • Elena Grau-García
  • Jose A. Román-Ivorra
  • José Luis Lopez-Paz
  • Jorge Escorihuela
  • Rosa Puchades
  • Sergi Morais
  • David Gimenez-Romero
  • Ángel Maquieira
Research Paper
  • 99 Downloads
Part of the following topical collections:
  1. Young Investigators in (Bio-)Analytical Chemistry

Abstract

The mechanism of self-recognition of the autoantigen TROVE2, a common biomarker in autoimmune diseases, has been studied with a quartz crystal microbalance with dissipation monitoring (QCM-D) and dual polarization interferometry (DPI). The complementarity and remarkable analytical features of both techniques has allowed new insights into the onset of systemic lupus erythematosus (SLE) to be achieved at the molecular level. The in vitro study for SLE patients and healthy subjects suggests that anti-TROVE2 autoantibodies may undergo an antibody bipolar bridging. An epitope-paratope-specific binding initially occurs to activate a hidden Fc receptor in the TROVE2 tertiary structure. This bipolar mechanism may contribute to the pathogenic accumulation of anti-TROVE2 autoantibody immune complex in autoimmune disease. Furthermore, the specific calcium-dependent protein-protein bridges point out at how the TRIM21/TROVE2 association might occur, suggesting that the TROVE2 protein could stimulate the intracellular immune signaling via the TRIM21 PRY-SPRY domain. These findings may help to better understand the origins of the specificity and affinity of TROVE2 interactions, which might play a key role in the SLE pathogenesis. This manuscript gives one of the first practical applications of two novel functions (−df/dD and Δh/molec) for the analysis of the data provided by QCM-D and DPI. In addition, it is the first time that QCM-D has been used for mapping hidden Fc receptors as well as linear epitopes in a protein tertiary structure.

Graphical abstract

Keywords

TROVE2 Antibody bipolar bridging Systemic lupus erythematosus Epitope mapping QCM-D Dual polarization interferometry 

Notes

Acknowledgements

We would like to thank Sylvia Daunert for her invaluable help with the discussion of the paper.

Funding information

Furthermore, we acknowledge financial support from the Generalitat Valenciana (GVA-PROMETEOII/2014/040) as well as the Spanish Ministry of Economy and Competitiveness and the European Regional Development Fund under award numbers CTQ2013-45875-R and CTQ2013-42914-R.

Compliance with ethical standards

Competing interests

The authors declare that they have no conflict of interest.

Supplementary material

216_2018_1407_MOESM1_ESM.pdf (1005 kb)
ESM 1 (PDF 0.98 MB)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Augusto Juste-Dolz
    • 1
  • Noelle M. do Nascimento
    • 1
  • Isidro Monzó
    • 2
  • Elena Grau-García
    • 3
  • Jose A. Román-Ivorra
    • 3
  • José Luis Lopez-Paz
    • 4
  • Jorge Escorihuela
    • 5
  • Rosa Puchades
    • 4
  • Sergi Morais
    • 4
  • David Gimenez-Romero
    • 2
  • Ángel Maquieira
    • 4
  1. 1.Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM)Universitat Politècnica de València, Universitat de ValènciaValenciaSpain
  2. 2.Departamento de Química-FísicaUniversitat de ValènciaBurjassotSpain
  3. 3.Departamento de Reumatología, Hospital Universitario y Politécnico La Fe, and Rheumatology Research GroupInstituto de Investigación Sanitaria La FeValenciaSpain
  4. 4.Departamento de QuímicaUniversitat Politècnica de ValènciaValenciaSpain
  5. 5.Departamento de Química OrgánicaUniversitat de ValènciaBurjassotSpain

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