The AIRE G228W mutation disturbs the interaction of AIRE with its partner molecule SIRT1

Autor(es)

Santos, Jadson C. ; Dametto, Mariangela ; Masson, Ana Paula ; Faca, Vitor M. ; Bonacin, Rodrigo ; Donadi, Eduardo A. ; Passos, Geraldo Aleixo

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN IMMUNOLOGY; v. 13, p. 10-pg., 2022-09-06.

Resumo

The autoimmune regulator (AIRE) protein functions as a tetramer, interacting with partner proteins to form the "AIRE complex," which relieves RNA Pol II stalling in the chromatin of medullary thymic epithelial cells (mTECs). AIRE is the primary mTEC transcriptional controller, promoting the expression of a large set of peripheral tissue antigen genes implicated in the negative selection of self-reactive thymocytes. Under normal conditions, the SIRT1 protein temporarily interacts with AIRE and deacetylates K residues of the AIRE SAND domain. Once the AIRE SAND domain is deacetylated, the binding with SIRT1 is undone, allowing the AIRE complex to proceed downstream with the RNA Pol II to the elongation phase of transcription. Considering that the in silico and in vitro binding of the AIRE SAND domain with SIRT1 provides a powerful model system for studying the dominant SAND G228W mutation mechanism, which causes the autoimmune polyglandular syndrome-1, we integrated computational molecular modeling, docking, dynamics between the whole SAND domain with SIRT1, and surface plasmon resonance using a peptide harboring the 211 to 230 residues of the SAND domain, to compare the structure and energetics of binding/release between AIRE G228 (wild-type) and W228 (mutant) SAND domain to SIRT1. We observed that the G228W mutation in the SAND domain negatively influences the AIRE-SIRT1 interaction. The disturbed interaction might cause a disruption in the binding of the AIRE SAND domain with the SIRT1 catalytic site, impairing the AIRE complex to proceed downstream with RNA Pol II. (AU)

• Processo FAPESP: 17/10780-4 - Efeito de mutações no gene AIRE (síndrome APS1) induzidas por CRISPR-Cas9 na conformação da proteína, no transcriptoma de células mTEC e na sua interação com timócitos
• Beneficiário: Geraldo Aleixo da Silva Passos Júnior
• Modalidade de apoio: Auxílio à Pesquisa - Temático