000099765 001__ 99765
000099765 005__ 20231027130639.0
000099765 0247_ $$2doi$$a10.1155/2021/6673661
000099765 0248_ $$2sideral$$a123304
000099765 037__ $$aART-2021-123304
000099765 041__ $$aeng
000099765 100__ $$aRomero-Tamayo, S.
000099765 245__ $$aW196 and the ß -Hairpin Motif Modulate the Redox Switch of Conformation and the Biomolecular Interaction Network of the Apoptosis-Inducing Factor
000099765 260__ $$c2021
000099765 5060_ $$aAccess copy available to the general public$$fUnrestricted
000099765 5203_ $$aThe human apoptosis-inducing factor (hAIF) is a moonlight flavoprotein involved in mitochondrial respiratory complex assembly and caspase-independent programmed cell death. These functions might be modulated by its redox-linked structural transition that enables hAIF to act as a NAD(H/+) redox sensor. Upon reduction with NADH, hAIF undergoes a conformational reorganization in two specific insertions - the flexible regulatory C-loop and the 190-202 ß-harpin - promoting protein dimerization and the stabilization of a long-life charge transfer complex (CTC) that modulates its monomer-dimer equilibrium and its protein interaction network in healthy mitochondria. In this regard, here, we investigated the precise function of the ß-hairpin in the AIF conformation landscape related to its redox mechanism, by analyzing the role played by W196, a key residue in the interaction of this motif with the regulatory C-loop. Mutations at W196 decrease the compactness and stability of the oxidized hAIF, indicating that the ß-hairpin and C-loop coupling contribute to protein stability. Kinetic studies complemented with computational simulations reveal that W196 and the ß-hairpin conformation modulate the low efficiency of hAIF as NADH oxidoreductase, contributing to configure its active site in a noncompetent geometry for hydride transfer and to stabilize the CTC state by enhancing the affinity for NAD+. Finally, the ß-hairpin motif contributes to define the conformation of AIF's interaction surfaces with its physiological partners. These findings improve our understanding on the molecular basis of hAIF''s cellular activities, a crucial aspect for clarifying its associated pathological mechanisms and developing new molecular therapies.
000099765 536__ $$9info:eu-repo/grantAgreement/ES/DGA/ARAID$$9info:eu-repo/grantAgreement/ES/DGA-FEDER/E35-20R$$9info:eu-repo/grantAgreement/ES/MICINN-AEI/PID2019-103901GB-I00$$9info:eu-repo/grantAgreement/ES/MINECO-AEI-FEDER/BIO2016-75183-P
000099765 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000099765 590__ $$a7.31$$b2021
000099765 592__ $$a1.233$$b2021
000099765 594__ $$a9.3$$b2021
000099765 591__ $$aCELL BIOLOGY$$b55 / 195 = 0.282$$c2021$$dQ2$$eT1
000099765 593__ $$aBiochemistry$$c2021$$dQ1
000099765 593__ $$aMedicine (miscellaneous)$$c2021$$dQ1
000099765 593__ $$aCell Biology$$c2021$$dQ1
000099765 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000099765 700__ $$aLaplaza, R.
000099765 700__ $$0(orcid)0000-0001-5702-4538$$aVelazquez-Campoy, A.$$uUniversidad de Zaragoza
000099765 700__ $$0(orcid)0000-0001-6676-9478$$aVillanueva, R.
000099765 700__ $$0(orcid)0000-0001-8743-0182$$aMedina, M.$$uUniversidad de Zaragoza
000099765 700__ $$0(orcid)0000-0003-4076-6118$$aFerreira, P.$$uUniversidad de Zaragoza
000099765 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000099765 773__ $$g2021 (2021), 6673661 [19 pp]$$pOxidative Medicine and Cellular Longevity$$tOxidative Medicine and Cellular Longevity$$x1942-0900
000099765 8564_ $$s1775979$$uhttps://zaguan.unizar.es/record/99765/files/texto_completo.pdf$$yVersión publicada
000099765 8564_ $$s2344364$$uhttps://zaguan.unizar.es/record/99765/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000099765 909CO $$ooai:zaguan.unizar.es:99765$$particulos$$pdriver
000099765 951__ $$a2023-10-27-12:53:36
000099765 980__ $$aARTICLE