The Jumonji-C oxygenase JMJD7 catalyzes (3S)-lysyl hydroxylation of TRAFAC GTPases

SUZANA MARKOLOVIC; QINQIN ZHUANG; SARAH E WILKINS; CHARLOTTE EATON; MARTINE I ABBOUD; MAXIMILIANO J KATZ; HELEN E SMITH; ROBERT K LEśNIAK; CHARLOTTE HALL; WESTON B STRUWE; REBECCA KONIETZNY; SIMON DAVIS; MING YANG; WEI GE; JUSTIN L BENESCH; BENEDIKT M KESSLER; PETER J RATCLIFFE; MATTHEW E COCKMAN; ROMAN FISCHER; PABLO WAPPNER; RASHEDUZZAMAN CHOWDHURY; MATHEW L COLEMAN; CHRISTOPHER J SCHOFIELD

NATURE CHEMICAL BIOLOGY

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2018

1552-4450

Biochemical, structural, and cellular studies reveal Jumonji-C (JmjC) domain-containing 7 (JMJD7) as a 2-oxoglutarate (2OG)-dependent oxygenase catalyzing a previously unreported type of post translational modification, (3S)-lysyl hydroxylation. Crystallographic analyses reveal JMJD7 as more closely related to the JmjC hydroxylases rather than the JmjC demethylases. Biophysical and mutation studies show that JMJD7 has a unique dimerization mode, with interactions between monomers involving both N- and C-terminal regions and disulfide bond formation. A proteomic approach identifies two related members of the Translation Factor (TRAFAC) family of GTPases, Developmentally Regulated GTP Binding Proteins 1 and 2 (DRG1/2), as activity-dependent JMJD7 interactors. Mass spectrometric analyses demonstrate that JMJD7 catalyzes Fe(II)- and 2OG-dependent hydroxylation of a highly-conserved lysine residue in DRG1/2; amino acid analyses reveal JMJD7 catalyzes (3S)-lysyl hydroxylation. The functional assignment of JMJD7 will enable future studies to define the role of DRG hydroxylation in cell growth and disease.