Abstract:
:The J-binding protein 1 (JBP1) is essential for biosynthesis and maintenance of DNA base-J (β-d-glucosyl-hydroxymethyluracil). Base-J and JBP1 are confined to some pathogenic protozoa and are absent from higher eukaryotes, prokaryotes and viruses. We show that JBP1 recognizes J-containing DNA (J-DNA) through a 160-residue domain, DB-JBP1, with 10 000-fold preference over normal DNA. The crystal structure of DB-JBP1 revealed a helix-turn-helix variant fold, a 'helical bouquet' with a 'ribbon' helix encompassing the amino acids responsible for DNA binding. Mutation of a single residue (Asp525) in the ribbon helix abrogates specificity toward J-DNA. The same mutation renders JBP1 unable to rescue the targeted deletion of endogenous JBP1 genes in Leishmania and changes its distribution in the nucleus. Based on mutational analysis and hydrogen/deuterium-exchange mass-spectrometry data, a model of JBP1 bound to J-DNA was constructed and validated by small-angle X-ray scattering data. Our results open new possibilities for targeted prevention of J-DNA recognition as a therapeutic intervention for parasitic diseases.
journal_name
Nucleic Acids Resjournal_title
Nucleic acids researchauthors
Heidebrecht T,Christodoulou E,Chalmers MJ,Jan S,Ter Riet B,Grover RK,Joosten RP,Littler D,van Luenen H,Griffin PR,Wentworth P Jr,Borst P,Perrakis Adoi
10.1093/nar/gkr125subject
Has Abstractpub_date
2011-07-01 00:00:00pages
5715-28issue
13eissn
0305-1048issn
1362-4962pii
gkr125journal_volume
39pub_type
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