6TP5

Crystal structure of human Transmembrane prolyl 4-hydroxylase

6TP5 の概要

• エントリーDOI: 10.2210/pdb6tp5/pdb
• 分子名称: Transmembrane prolyl 4-hydroxylase, CHLORIDE ION, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (11 entities in total)
• 機能のキーワード: prolyl-4-hydroxylase, 2-oxoglutarate-binding protein, transmembrane protein, ef-hand, double-stranded beta helix, iron-binding protein, calcium-binding protein, hidea syndrome, oxidoreductase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 102370.33

構造登録者

Myllykoski, M.,Sutinen, A.,Koski, M.K.,Kallio, J.P.,Raasakka, A.,Myllyharju, J.,Wierenga, R.K.,Koivunen, P. (登録日: 2019-12-12, 公開日: 2020-12-23, 最終更新日: 2024-10-23)

主引用文献

Myllykoski, M.,Sutinen, A.,Koski, M.K.,Kallio, J.P.,Raasakka, A.,Myllyharju, J.,Wierenga, R.K.,Koivunen, P.
Structure of transmembrane prolyl 4-hydroxylase reveals unique organization of EF and dioxygenase domains.
J.Biol.Chem., 296:100197-100197, 2020

PubMed Abstract: Prolyl 4-hydroxylases (P4Hs) catalyze post-translational hydroxylation of peptidyl proline residues. In addition to collagen P4Hs and hypoxia-inducible factor P4Hs, a third P4H-the poorly characterized endoplasmic reticulum-localized transmembrane prolyl 4-hydroxylase (P4H-TM)-is found in animals. P4H-TM variants are associated with the familiar neurological HIDEA syndrome, but how these variants might contribute to disease is unknown. Here, we explored this question in a structural and functional analysis of soluble human P4H-TM. The crystal structure revealed an EF domain with two Ca-binding motifs inserted within the catalytic domain. A substrate-binding groove was formed between the EF domain and the conserved core of the catalytic domain. The proximity of the EF domain to the active site suggests that Ca binding is relevant to the catalytic activity. Functional analysis demonstrated that Ca-binding affinity of P4H-TM is within the range of physiological Ca concentration in the endoplasmic reticulum. P4H-TM was found both as a monomer and a dimer in the solution, but the monomer-dimer equilibrium was not regulated by Ca. The catalytic site contained bound Fe and N-oxalylglycine, which is an analogue of the cosubstrate 2-oxoglutarate. Comparison with homologous P4H structures complexed with peptide substrates showed that the substrate-interacting residues and the lid structure that folds over the substrate are conserved in P4H-TM, whereas the extensive loop structures that surround the substrate-binding groove, generating a negative surface potential, are different. Analysis of the structure suggests that the HIDEA variants cause loss of P4H-TM function. In conclusion, P4H-TM shares key structural elements with other P4Hs while having a unique EF domain.

PubMed: 33334883
DOI: 10.1074/jbc.RA120.016542

実験手法

X-RAY DIFFRACTION (2.25 Å)