170402 20260420103354.0 doi 10.1016/j.ijbiomac.2026.151719 sideral 148912 ART-2026-148912 eng Di Napoli, Giulia Calcium as a molecular switch that regulates Annexin A11 N- and C-terminal domains interaction and its role in ALS 2026 Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease marked by progressive motor neuron loss, leading to muscle paralysis and respiratory failure. Genetic mutations, notably in the ANXA11 gene, have been implicated in both familial and sporadic ALS forms. ANXA11 functions as a cellular “tether,” orchestrating the transport of RNA-protein complexes and lysosomes through its N-terminal (Nt) and C-terminal (Ct) domains, respectively. This study uncovers a novel calcium-dependent regulatory mechanism governing the intramolecular interaction between these domains. Using biochemical, biophysical, and computational approaches, we suggest that in the absence of calcium, ANXA11 adopts a closed conformation with stable Nt-Ct interactions. Elevated calcium levels induce a conformational shift, disrupting this interaction and exposing binding sites for RNA and membranes. Crucially, we show that the ALS-associated D40G mutation in the Nt domain impairs this calcium-regulated interaction, favoring a persistent open conformation that predisposes to toxic protein aggregation. These findings reveal that calcium acts as a molecular switch modulating ANXA11 conformation and function, providing new insights into its role in ALS pathogenesis and potential therapeutic targets. Access copy available to the general public Unrestricted info:eu-repo/semantics/openAccess by https://creativecommons.org/licenses/by/4.0/deed.es info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Alfurno, Lorenzo Fissore, Alex Raccuia, Eleonora Olivieri, Paolo Marengo, Mauro Oliaro-Bosso, Simonetta Piaz, Fabrizio Dal Catucci, Gianluca Gilardi, Gianfranco Velazquez-Campoy, Adrian Universidad de Zaragoza (orcid)0000-0001-5702-4538 Prischi, Filippo De Simone, Angela Spyrakis, Francesca Di Palma, Francesco Adinolfi, Salvatore 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 358, [9 pp.] (2026), 151719 Int. j. biol. macromol. International journal of biological macromolecules 0141-8130 4107834 http://zaguan.unizar.es/record/170402/files/texto_completo.pdf Versión publicada 2329184 http://zaguan.unizar.es/record/170402/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:170402 articulos driver 2026-04-18-10:48:53 ARTICLE