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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

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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.

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Acknowledgements

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

Funding

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.

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Authors and Affiliations

  1. Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Universitat Politècnica de València, Universitat de València, 46022, Valencia, Spain

    Augusto Juste-Dolz & Noelle M. do Nascimento

  2. Departamento de Química-Física, Universitat de València, C/ Dr. Moliner 50, 46100, Burjassot, Spain

    Isidro Monzó & David Gimenez-Romero

  3. Departamento de Reumatología, Hospital Universitario y Politécnico La Fe, and Rheumatology Research Group, Instituto de Investigación Sanitaria La Fe, Avenida de Fernando Abril Martorell No 106, 46026, Valencia, Spain

    Elena Grau-García & Jose A. Román-Ivorra

  4. Departamento de Química, Universitat Politècnica de València, 46022, Valencia, Spain

    José Luis Lopez-Paz, Rosa Puchades, Sergi Morais & Ángel Maquieira

  5. Departamento de Química Orgánica, Universitat de València, C/ Dr. Moliner 50, 46100, Burjassot, Spain

    Jorge Escorihuela

Authors
  1. Augusto Juste-Dolz
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  2. Noelle M. do Nascimento
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Correspondence to David Gimenez-Romero or Ángel Maquieira.

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Published in the topical collection Young Investigators in (Bio-)Analytical Chemistry with guest editors Erin Baker, Kerstin Leopold, Francesco Ricci, and Wei Wang.

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Juste-Dolz, A., do Nascimento, N.M., Monzó, I. et al. 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. Anal Bioanal Chem 411, 4709–4720 (2019). https://doi.org/10.1007/s00216-018-1407-x

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