6zk7 | pdb_00006zk7
Crystal Structure of human PYROXD1/FAD complex
Structural highlights
Disease[PYRD1_HUMAN] The disease is caused by variants affecting the gene represented in this entry. A mutation in PYROXD1 is the cause of autosomal recessive limb-girdle muscular dystrophy. The affected individual with a homozygous recessive PYROXD1 mutation showed progressive muscle weakness with an onset at the age of 9 years. Initial symptoms included excessive falling while running, with slowly progressive weakness. Difficulty navigating stairs by the age if 18, and loss of ambulation at the age of 37 years. Neurological examination showed proximal symmetrical muscle weakness and wasting, along with calf muscle pseudohypertrophy.[1] Function[PYRD1_HUMAN] Probable FAD-dependent oxidoreductase; involved in the cellular oxidative stress response (PubMed:27745833). Required for normal sarcomere structure and muscle fiber integrity (By similarity).[UniProtKB:Q6PBT5][2] Publication Abstract from PubMedThe tRNA ligase complex (tRNA-LC) splices precursor tRNAs (pre-tRNA), and Xbp1-mRNA during the unfolded protein response (UPR). In aerobic conditions, a cysteine residue bound to two metal ions in its ancient, catalytic subunit RTCB could make the tRNA-LC susceptible to oxidative inactivation. Here, we confirm this hypothesis and reveal a co-evolutionary association between the tRNA-LC and PYROXD1, a conserved and essential oxidoreductase. We reveal that PYROXD1 preserves the activity of the mammalian tRNA-LC in pre-tRNA splicing and UPR. PYROXD1 binds the tRNA-LC in the presence of NAD(P)H and converts RTCB-bound NAD(P)H into NAD(P)(+), a typical oxidative co-enzyme. However, NAD(P)(+) here acts as an antioxidant and protects the tRNA-LC from oxidative inactivation, which is dependent on copper ions. Genetic variants of PYROXD1 that cause human myopathies only partially support tRNA-LC activity. Thus, we establish the tRNA-LC as an oxidation-sensitive metalloenzyme, safeguarded by the flavoprotein PYROXD1 through an unexpected redox mechanism. The oxidoreductase PYROXD1 uses NAD(P)(+) as an antioxidant to sustain tRNA ligase activity in pre-tRNA splicing and unfolded protein response.,Asanovic I, Strandback E, Kroupova A, Pasajlic D, Meinhart A, Tsung-Pin P, Djokovic N, Anrather D, Schuetz T, Suskiewicz MJ, Sillamaa S, Kocher T, Beveridge R, Nikolic K, Schleiffer A, Jinek M, Hartl M, Clausen T, Penninger J, Macheroux P, Weitzer S, Martinez J Mol Cell. 2021 Apr 23. pii: S1097-2765(21)00312-9. doi:, 10.1016/j.molcel.2021.04.007. PMID:33930333[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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