000170402 001__ 170402
000170402 005__ 20260420103354.0
000170402 0247_ $$2doi$$a10.1016/j.ijbiomac.2026.151719
000170402 0248_ $$2sideral$$a148912
000170402 037__ $$aART-2026-148912
000170402 041__ $$aeng
000170402 100__ $$aDi Napoli, Giulia
000170402 245__ $$aCalcium as a molecular switch that regulates Annexin A11 N- and C-terminal domains interaction and its role in ALS
000170402 260__ $$c2026
000170402 5060_ $$aAccess copy available to the general public$$fUnrestricted
000170402 5203_ $$aAmyotrophic 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.
000170402 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttps://creativecommons.org/licenses/by/4.0/deed.es
000170402 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000170402 700__ $$aAlfurno, Lorenzo
000170402 700__ $$aFissore, Alex
000170402 700__ $$aRaccuia, Eleonora
000170402 700__ $$aOlivieri, Paolo
000170402 700__ $$aMarengo, Mauro
000170402 700__ $$aOliaro-Bosso, Simonetta
000170402 700__ $$aPiaz, Fabrizio Dal
000170402 700__ $$aCatucci, Gianluca
000170402 700__ $$aGilardi, Gianfranco
000170402 700__ $$0(orcid)0000-0001-5702-4538$$aVelazquez-Campoy, Adrian$$uUniversidad de Zaragoza
000170402 700__ $$aPrischi, Filippo
000170402 700__ $$aDe Simone, Angela
000170402 700__ $$aSpyrakis, Francesca
000170402 700__ $$aDi Palma, Francesco
000170402 700__ $$aAdinolfi, Salvatore
000170402 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000170402 773__ $$g358, [9 pp.] (2026), 151719$$pInt. j. biol. macromol.$$tInternational journal of biological macromolecules$$x0141-8130
000170402 8564_ $$s4107834$$uhttps://zaguan.unizar.es/record/170402/files/texto_completo.pdf$$yVersión publicada
000170402 8564_ $$s2329184$$uhttps://zaguan.unizar.es/record/170402/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000170402 909CO $$ooai:zaguan.unizar.es:170402$$particulos$$pdriver
000170402 951__ $$a2026-04-18-10:48:53
000170402 980__ $$aARTICLE