000088505 001__ 88505
000088505 005__ 20201215123134.0
000088505 0247_ $$2doi$$a10.1089/ars.2018.7658
000088505 0248_ $$2sideral$$a112210
000088505 037__ $$aART-2019-112210
000088505 041__ $$aeng
000088505 100__ $$0(orcid)0000-0001-6676-9478$$aVillanueva, Raquel
000088505 245__ $$aRedox-and ligand binding-dependent conformational ensembles in the human apoptosis-inducing factor regulate its pro-life and cell death functions
000088505 260__ $$c2019
000088505 5060_ $$aAccess copy available to the general public$$fUnrestricted
000088505 5203_ $$aAims: The human apoptosis-inducing factor (hAIF) supports OXPHOS biogenesis and programmed cell death, with missense mutations producing neurodegenerative phenotypes. hAIF senses the redox environment of cellular compartments, stabilizing a charge transfer complex (CTC) dimer that modulates the protein interaction network. In this context, we aimed to evaluate the subcellular pH, CTC formation, and pathogenic mutations effects on hAIF stability, and a thermal denaturation high-throughput screening (HTS) assay to discover AIF binders.
Results: Apoptotic hAIF(Delta 1-101) is not stable at intermembrane mitochondrial space (IMS) pH, but the 77-101 residues confer stability to the mitochondrial isoform. hAIF and its CTC populate different conformational ensembles with redox switch to the CTC producing a less stable and compact protein. The pathogenic G308E, Delta R201, and E493V mutations modulate hAIF stability; particularly, Delta R201 causes a population shift to a less stable conformation that remodels active site structure and dynamics. We have identified new molecules that modulate the hAIF reduced nicotinamide adenine dinucleotide (NADH)/oxidized nicotinamide adenine dinucleotide (NAD(+)) association/dissociation equilibrium and regulate its catalytic efficiency.
Innovation: Biophysical methods allow evaluating the regulation of hAIF functional ensembles and to develop an HTS assay to discover small molecules that might modulate hAIF stability and activities.
Conclusions: The mitochondrial soluble 54-77 portion stabilizes hAIF at the IMS pH. NADH-redox-linked conformation changes course with strong NAD(+) binding and protein dimerization, but they produce a negative impact in overall hAIF stability. Loss of functionality in the R201 deletion is due to distortion of the active site architecture. We report molecules that may serve as leads in the development of hAIF bioactive compounds.
000088505 536__ $$9info:eu-repo/grantAgreement/ES/DGA/E35-17R$$9info:eu-repo/grantAgreement/ES/DGA/E45-17R$$9info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P$$9info:eu-repo/grantAgreement/ES/MINECO-FEDER/BIO2016-75183-P
000088505 540__ $$9info:eu-repo/semantics/openAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/
000088505 590__ $$a7.04$$b2019
000088505 592__ $$a2.163$$b2019
000088505 591__ $$aENDOCRINOLOGY & METABOLISM$$b13 / 143 = 0.091$$c2019$$dQ1$$eT1
000088505 593__ $$aBiochemistry$$c2019$$dQ1
000088505 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b35 / 297 = 0.118$$c2019$$dQ1$$eT1
000088505 593__ $$aCell Biology$$c2019$$dQ1
000088505 593__ $$aPhysiology$$c2019$$dQ1
000088505 593__ $$aMedicine (miscellaneous)$$c2019$$dQ1
000088505 593__ $$aMolecular Biology$$c2019$$dQ1
000088505 593__ $$aClinical Biochemistry$$c2019$$dQ1
000088505 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/acceptedVersion
000088505 700__ $$aRomero-Tamayo, Silvia$$uUniversidad de Zaragoza
000088505 700__ $$aLaplaza, Ruben
000088505 700__ $$0(orcid)0000-0002-8784-7735$$aMartinez-Olivan, Juan
000088505 700__ $$0(orcid)0000-0001-5702-4538$$aVelazquez-Campoy, Adrián$$uUniversidad de Zaragoza
000088505 700__ $$0(orcid)0000-0002-2879-9200$$aSancho, Javier$$uUniversidad de Zaragoza
000088505 700__ $$0(orcid)0000-0003-4076-6118$$aFerreira, Patricia$$uUniversidad de Zaragoza
000088505 700__ $$0(orcid)0000-0001-8743-0182$$aMedina, Milagros$$uUniversidad de Zaragoza
000088505 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000088505 773__ $$g30, 18 (2019), 2013-2029$$pAntioxid. redox signal.$$tAntioxidants & redox signaling$$x1523-0864
000088505 8564_ $$s5844596$$uhttps://zaguan.unizar.es/record/88505/files/texto_completo.pdf$$yPostprint
000088505 8564_ $$s1697$$uhttps://zaguan.unizar.es/record/88505/files/texto_completo.jpg?subformat=icon$$xicon$$yPostprint
000088505 909CO $$ooai:zaguan.unizar.es:88505$$particulos$$pdriver
000088505 951__ $$a2020-12-15-12:29:31
000088505 980__ $$aARTICLE