Structural Study of a Peptide Epitope Bearing Multiple Post-Translational Modifications in Rheumatoid Arthritis
Gómara, María José (Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC)
García-Moreno, Cristina (Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC)
Bárcenas, Oriol (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Castellanos-Moreira, Raúl (Hospital Clínic i Provincial de Barcelona)
Sarmiento, Juan Camilo (Hospital Clínic i Provincial de Barcelona)
Crehuet, Ramon (Computational and Theoretical Chemistry Group, IQAC-CSIC)
Pérez, Yolanda (NMR Facility, IQAC-CSIC)
Sanmartí, Raimon (Hospital Clínic i Provincial de Barcelona)
Haro, Isabel (Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC)

Fecha:	2025
Resumen:	Given the limited knowledge of the effect of post-translational modifications (PTMs) on protein structure, in this study we investigated whether introducing one-to-three RA-related PTMs into the α-fibrin (617-631) peptide influences the conformation and structure of the peptide antigen that could be responsible for the autoantibody recognition. Ten peptides containing a different number of PTMs within their primary structure were synthesized and their recognition by sera from RA patients was analyzed. The conformation of the peptides was studied by circular dichroism (CD) and the structure of the most relevant antigenic peptides was determined by nuclear magnetic resonance (NMR) and enhanced-sampling molecular dynamics (MD). Although peptides containing citrulline (Cit) showed a higher degree of binding to AMPAs than peptides containing only homocitrulline and/or acetyl-lysine, the latter were able to bind to AMPAs in sera that showed a small response to peptides with Cit, with the response being different depending on the position of each PTM. CD and NMR analyses indicated a series of half-turn conformations in the Lys620-Arg630 region. MD simulations generated a set of conformations compatible with the NMR NOEs. The effect of the PTMs was observed in intra-molecular contacts, hydrogen bonds and van der Waals interactions, generating more collapsed conformations. Differences in autoantibody reactivity between peptides bearing different PTMs within their primary structures are noted. Peptides with PTMs adopt different conformations than unmodified peptides, probably due to the lower net charge of peptides with multiple PTMs, which may explain their recognition by autoantibodies.
Ayudas:	Agencia Estatal de Investigación PID2021-122216OB-I00
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	RA ; Α-fibrin (617-631) peptides ; PTMs ; AMPAs ; CD ; NMR ; MD ; Conformation ; Structure
Publicado en:	International journal of molecular sciences, Vol. 26, Num. 18 (September 2025) , art. 9026, ISSN 1422-0067

DOI: 10.3390/ijms26189026
PMID: 41009593

18 p, 2.2 MB

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