Intrinsically disordered regions in atypical dual-specificity phosphatases: A review

Autor(es)

Pacheco, Diana R. D. C. G. ; Forti, Sofia F. ; Forti, Fabio L.

• Tipo de documento: Artigo Científico
• Fonte: International Journal of Biological Macromolecules; v. 323, p. 14-pg., 2025-09-01.

Resumo

Intrinsically disordered regions (IDRs) are conserved elements that enable cellular adaptability by mediating rapid responses to environmental cues. Their biophysical properties-disorder-to-order transitions, phase separation, and interaction versatility-are vital for protein localization, signaling, and disease mechanisms. In protein tyrosine phosphatases (PTPs), and notably dual-specificity phosphatases (DUSPs), IDRs serve functional roles beyond passive linkers. Atypical DUSPs (ADUSPs) utilize IDRs instead of rigid domains for substrate recruitment, autoinhibition, and spatiotemporal regulation of MAPK pathways, granting them functional plasticity to integrate diverse signals via post-translational modifications (PTMs) and environmental sensing. Critical questions remain: (1) how PTMs modulate DUSP IDR conformation and activity; (2) the potential for therapeutics targeting IDR-mediated interactions in diseases like cancer and neurodegeneration; (3) whether DUSP IDRs form phase-separated signaling complexes during stress. Addressing these issues require multidisciplinary approaches-Cryo-EM, NMR, SAXS, smFRET, computational modeling, CD, SEC-MALS, HDX-MS, and LiPMS-to elucidate transient conformations, dynamics, and interactions. Insights into IDR-mediated regulation in atypical DUSPs could revolutionize therapeutic strategies, shifting from active-site targeting to exploiting the conformational plasticity of these dynamic, regulatory regions. (AU)

• Processo FAPESP: 24/13597-0 - Quimio e radioresistência de glioblastomas: o papel da fosfatase DUSP12 e da GTPase Rho
• Beneficiário: Fábio Luis Forti
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 22/10958-6 - Estudos bioquímicos da fosfatase DUSP12 em condições de estresse genotóxico: interações bimoleculares e atividade enzimática
• Beneficiário: Diana Reis Della Corte Guimarães Pacheco
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto