6ZK7

Crystal Structure of human PYROXD1/FAD complex

This is a non-PDB format compatible entry.

Summary for 6ZK7

• Entry DOI: 10.2210/pdb6zk7/pdb
• Descriptor: Pyridine nucleotide-disulfide oxidoreductase domain-containing protein 1, FLAVIN-ADENINE DINUCLEOTIDE (2 entities in total)
• Functional Keywords: redox regulation, nad(p)(h) binding, trna ligase complex, flavoprotein, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 57763.12

Authors

Meinhart, A.,Asanovic, I.,Martinez, J.,Clausen, T. (deposition date: 2020-06-30, release date: 2021-05-12, Last modification date: 2024-10-16)

Primary citation

Asanovic, I.,Strandback, E.,Kroupova, A.,Pasajlic, D.,Meinhart, A.,Tsung-Pin, P.,Djokovic, N.,Anrather, D.,Schuetz, T.,Suskiewicz, M.J.,Sillamaa, S.,Kocher, T.,Beveridge, R.,Nikolic, K.,Schleiffer, A.,Jinek, M.,Hartl, M.,Clausen, T.,Penninger, J.,Macheroux, P.,Weitzer, S.,Martinez, J.
The oxidoreductase PYROXD1 uses NAD(P) + as an antioxidant to sustain tRNA ligase activity in pre-tRNA splicing and unfolded protein response.
Mol.Cell, 81:2520-, 2021

PubMed Abstract: The 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.

PubMed: 33930333
DOI: 10.1016/j.molcel.2021.04.007

Experimental method

X-RAY DIFFRACTION (3.2 Å)