4iqm

From Proteopedia

Crystal structure of the catalytic domain of human Pus1

PDB ID 4iqm

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Structural highlights

4iqm is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.8Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PUS1_HUMAN Mitochondrial myopathy and sideroblastic anemia. The disease is caused by variants affecting the gene represented in this entry.

Function

PUS1_HUMAN Pseudouridylate synthase that catalyzes pseudouridylation of tRNAs and mRNAs (PubMed:15772074, PubMed:24722331). Acts on positions 27/28 in the anticodon stem and also positions 34 and 36 in the anticodon of an intron containing tRNA (PubMed:24722331). Also catalyzes pseudouridylation of mRNAs: mediates pseudouridylation of mRNAs with the consensus sequence 5'-UGUAG-3' (PubMed:31477916, PubMed:35051350). Acts as a regulator of pre-mRNA splicing by mediating pseudouridylation of pre-mRNAs at locations associated with alternatively spliced regions (PubMed:35051350). Pseudouridylation of pre-mRNAs near splice sites directly regulates mRNA splicing and mRNA 3'-end processing (PubMed:35051350). Involved in regulation of nuclear receptor activity through pseudouridylation of SRA1 mRNA (PubMed:24722331).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Human pseudouridine (Psi) synthase Pus1 (hPus1) modifies specific uridine residues in several non-coding RNAs: tRNA, U2 spliceosomal RNA, and steroid receptor activator RNA. We report three structures of the catalytic core domain of hPus1 from two crystal forms, at 1.8A resolution. The structures are the first of a mammalian Psi synthase from the set of five Psi-synthase families common to all kingdoms of life. Pus1 adopts a fold similar to bacterial Psi synthases, with a central antiparallel beta-sheet flanked by helices and loops. A flexible hinge at the base of the sheet allows the enzyme to open and close around an electropositive active-site cleft. In one crystal form, a molecule of Mes [2-(N-morpholino)ethane sulfonic acid] mimics the target uridine of an RNA substrate. A positively charged electrostatic surface extends from the active site towards the N-terminus of the catalytic domain, suggesting an extensive binding site specific for target RNAs. Two alpha-helices C-terminal to the core domain, but unique to hPus1, extend along the back and top of the central beta-sheet and form the walls of the RNA binding surface. Docking of tRNA to hPus1 in a productive orientation requires only minor conformational changes to enzyme and tRNA. The docked tRNA is bound by the electropositive surface of the protein employing a completely different binding mode than that seen for the tRNA complex of the Escherichia coli homologue TruA.

In Human Pseudouridine Synthase 1 (hPus1), a C-Terminal Helical Insert Blocks tRNA from Binding in the Same Orientation as in the Pus1 Bacterial Homologue TruA, Consistent with Their Different Target Selectivities.,Czudnochowski N, Wang AL, Finer-Moore J, Stroud RM J Mol Biol. 2013 May 23. pii: S0022-2836(13)00328-8. doi:, 10.1016/j.jmb.2013.05.014. PMID:23707380^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Patton JR, Bykhovskaya Y, Mengesha E, Bertolotto C, Fischel-Ghodsian N. Mitochondrial myopathy and sideroblastic anemia (MLASA): missense mutation in the pseudouridine synthase 1 (PUS1) gene is associated with the loss of tRNA pseudouridylation. J Biol Chem. 2005 May 20;280(20):19823-8. doi: 10.1074/jbc.M500216200. Epub 2005 , Mar 16. PMID:15772074 doi:http://dx.doi.org/10.1074/jbc.M500216200
↑ Huet T, Miannay FA, Patton JR, Thore S. Steroid receptor RNA activator (SRA) modification by the human pseudouridine synthase 1 (hPus1p): RNA binding, activity, and atomic model. PLoS One. 2014 Apr 10;9(4):e94610. doi: 10.1371/journal.pone.0094610. eCollection, 2014. PMID:24722331 doi:http://dx.doi.org/10.1371/journal.pone.0094610
↑ Carlile TM, Martinez NM, Schaening C, Su A, Bell TA, Zinshteyn B, Gilbert WV. mRNA structure determines modification by pseudouridine synthase 1. Nat Chem Biol. 2019 Oct;15(10):966-974. doi: 10.1038/s41589-019-0353-z. Epub 2019, Sep 2. PMID:31477916 doi:http://dx.doi.org/10.1038/s41589-019-0353-z
↑ Martinez NM, Su A, Burns MC, Nussbacher JK, Schaening C, Sathe S, Yeo GW, Gilbert WV. Pseudouridine synthases modify human pre-mRNA co-transcriptionally and affect pre-mRNA processing. Mol Cell. 2022 Feb 3;82(3):645-659.e9. doi: 10.1016/j.molcel.2021.12.023. Epub, 2022 Jan 19. PMID:35051350 doi:http://dx.doi.org/10.1016/j.molcel.2021.12.023
↑ Czudnochowski N, Wang AL, Finer-Moore J, Stroud RM. In Human Pseudouridine Synthase 1 (hPus1), a C-Terminal Helical Insert Blocks tRNA from Binding in the Same Orientation as in the Pus1 Bacterial Homologue TruA, Consistent with Their Different Target Selectivities. J Mol Biol. 2013 May 23. pii: S0022-2836(13)00328-8. doi:, 10.1016/j.jmb.2013.05.014. PMID:23707380 doi:10.1016/j.jmb.2013.05.014