| Structural highlights
5mfa is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , , , |
| NonStd Res: | |
| Activity: | Myeloperoxidase, with EC number 1.11.2.2 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[PERM_HUMAN] Defects in MPO are the cause of myeloperoxidase deficiency (MPOD) [MIM:254600]. A disorder characterized by decreased myeloperoxidase activity in neutrophils and monocytes that results in disseminated candidiasis.[1] [2] [3] [4] [5]
Function
[PERM_HUMAN] Part of the host defense system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production of hypohalous acids, primarily hypochlorous acid in physiologic situations, and other toxic intermediates that greatly enhance PMN microbicidal activity.
Publication Abstract from PubMed
Myeloperoxidase (MPO) is synthesized by neutrophil and monocyte precursor cells and contributes to host defense by mediating microbial killing. Although several steps in MPO biosynthesis and processing have been elucidated, many questions remain, such as the structure-function relationships of monomeric unprocessed proMPO versus the mature dimeric MPO and the functional role of the propeptide. Here we present the first and high resolution (at 1.25 A) crystal structure of proMPO and its solution structure obtained by small angle X-ray scattering. Promyeloperoxidase hosts five occupied glycosylation sites and six intrachain cystine bridges with C158 of the very flexible N-terminal propeptide being covalently linked to C319 thereby hindering homodimerization. Furthermore, the structure revealed (i) the binding site of proMPO processing proconvertase, (ii) the structural motif for subsequent cleavage to the heavy and light chains of mature MPO protomers and (iii) three covalent bonds between heme and the protein. Studies on the mutants C158A, C319A and C158A/C319A demonstrate significant differences from the wild-type protein, including diminished enzymatic activity and prevention from export to the Golgi due to prolonged association with the chaperone calnexin. These structural and functional data provide novel insights into MPO biosynthesis and processing.
Structure of human promyeloperoxidase (proMPO) and the role of the propeptide for processing and maturation.,Grishkovskaya I, Paumann-Page M, Tscheliessnig R, Stampler J, Hofbauer S, Soudi M, Sevcnikar B, Oostenbrink C, Furtmuller PG, Djinovic-Carugo K, Nauseef WM, Obinger C J Biol Chem. 2017 Mar 27. pii: jbc.M117.775031. doi: 10.1074/jbc.M117.775031. PMID:28348079[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kizaki M, Miller CW, Selsted ME, Koeffler HP. Myeloperoxidase (MPO) gene mutation in hereditary MPO deficiency. Blood. 1994 Apr 1;83(7):1935-40. PMID:8142659
- ↑ Nauseef WM, Brigham S, Cogley M. Hereditary myeloperoxidase deficiency due to a missense mutation of arginine 569 to tryptophan. J Biol Chem. 1994 Jan 14;269(2):1212-6. PMID:7904599
- ↑ Nauseef WM, Cogley M, McCormick S. Effect of the R569W missense mutation on the biosynthesis of myeloperoxidase. J Biol Chem. 1996 Apr 19;271(16):9546-9. PMID:8621627
- ↑ DeLeo FR, Goedken M, McCormick SJ, Nauseef WM. A novel form of hereditary myeloperoxidase deficiency linked to endoplasmic reticulum/proteasome degradation. J Clin Invest. 1998 Jun 15;101(12):2900-9. PMID:9637725 doi:10.1172/JCI2649
- ↑ Romano M, Dri P, Dadalt L, Patriarca P, Baralle FE. Biochemical and molecular characterization of hereditary myeloperoxidase deficiency. Blood. 1997 Nov 15;90(10):4126-34. PMID:9354683
- ↑ Grishkovskaya I, Paumann-Page M, Tscheliessnig R, Stampler J, Hofbauer S, Soudi M, Sevcnikar B, Oostenbrink C, Furtmuller PG, Djinovic-Carugo K, Nauseef WM, Obinger C. Structure of human promyeloperoxidase (proMPO) and the role of the propeptide for processing and maturation. J Biol Chem. 2017 Mar 27. pii: jbc.M117.775031. doi: 10.1074/jbc.M117.775031. PMID:28348079 doi:http://dx.doi.org/10.1074/jbc.M117.775031
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