5MFA

Crystal structure of human promyeloperoxidase (proMPO)

Summary for 5MFA

• Entry DOI: 10.2210/pdb5mfa/pdb
• Descriptor: Myeloperoxidase, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (10 entities in total)
• Functional Keywords: myeloperoxidase, prompo, biosynthesis, proteolytic maturation, halide oxidation, oxidoreductase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 82736.11

Authors

Grishkovskaya, I.,Furtmueller, P.G.,Obinger, C.,Djinovic-Carugo, K. (deposition date: 2016-11-17, release date: 2017-04-05, Last modification date: 2024-01-17)

Primary citation

Grishkovskaya, I.,Paumann-Page, M.,Tscheliessnig, R.,Stampler, J.,Hofbauer, S.,Soudi, M.,Sevcnikar, B.,Oostenbrink, C.,Furtmuller, P.G.,Djinovic-Carugo, K.,Nauseef, W.M.,Obinger, C.
Structure of human promyeloperoxidase (proMPO) and the role of the propeptide in processing and maturation.
J. Biol. Chem., 292:8244-8261, 2017

PubMed Abstract: 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 remained, such as the structure-function relationship of monomeric unprocessed proMPO the mature dimeric MPO and the functional role of the propeptide. Here we have presented the first and high resolution (at 1.25 Å) 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 Cys-158 of the very flexible N-terminal propeptide being covalently linked to Cys-319 and 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 of the mutants C158A, C319A, and C158A/C319A demonstrated significant differences from the wild-type protein, including diminished enzymatic activity and prevention of export to the Golgi due to prolonged association with the chaperone calnexin. These structural and functional findings provide novel insights into MPO biosynthesis and processing.

PubMed: 28348079
DOI: 10.1074/jbc.M117.775031

Experimental method

X-RAY DIFFRACTION (1.2 Å)