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Structure-based domain assignment in Leishmania infantum EndoG: Characterization of a pH-dependent regulatory switch and a C-Terminal extension that largely dictates DNA substrate preferences

AutorOliva, C.; Sánchez-Murcia, Pedro A. ; Rico, E.; Bravo, A.; Menéndez, Margarita ; Gago, F.; Jiménez-Ruiz, A.
Fecha de publicación2017
EditorOxford University Press
CitaciónNucleic Acids Research 45: 9030- 9045 (2017)
ResumenMitochondrial endonuclease G from Leishmania infantum (LiEndoG) participates in the degradation of double-stranded DNA (dsDNA) during parasite cell death and is catalytically inactive at a pH of 8.0 or above. The presence, in the primary sequence, of an acidic amino acid-rich insertion exclusive to trypanosomatids and its spatial position in a homologybuilt model of LiEndoG led us to postulate that this peptide stretch might act as a pH sensor for selfinhibition. We found that a LiEndoG variant lacking residues 145-180 is indeed far more active than its wild-Type counterpart at pH values >7.0. In addition, we discovered that (i) LiEndoG exists as a homodimer, (ii) replacement of Ser211 in the active-site SRGH motif with the canonical aspartate from the DRGH motif of other nucleases leads to a catalytically deficient enzyme, (iii) the activity of the S211D variant can be restored upon the concomitant replacement of Ala247 with Arg and (iv) a C-Terminal extension is responsible for the observed preferential cleavage of single-stranded DNA (ssDNA) and ssDNA- dsDNA junctions. Taken together, our results support the view that LiEndoG is a multidomain molecular machine whose nuclease activity can be subtly modulated or even abrogated through architectural changes brought about by environmental conditions and interaction with other binding partners.
URIhttp://hdl.handle.net/10261/165817
Identificadoresdoi: 10.1093/nar/gkx629
issn: 1362-4962
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