Structural highlights
Disease
P4HA2_HUMAN The disease is caused by mutations affecting the gene represented in this entry.
Function
P4HA2_HUMAN Catalyzes the post-translational formation of 4-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens and other proteins.
Publication Abstract from PubMed
Collagen prolyl 4-hydroxylases (C-P4H) are alpha2beta2 tetramers, which catalyze the prolyl 4-hydroxylation of procollagen chains, allowing for the formation of the stable triple-helical collagen structure in the endoplasmic reticulum. The C-P4H alpha-subunit provides the N-terminal dimerization domain, the middle peptide-substrate-binding domain (PSB), and the C-terminal catalytic (CAT) domain, while the beta-subunit is identical to the enzyme protein disulfide isomerase (PDI). The structure of the N-terminal part of the alpha-subunit (N-terminal and PSB domain) is known, but the structures of the PSB-CAT linker region and the CAT domain as well as its mode of assembly with the beta/PDI-subunit, are not known. Here we report the crystal structure of the CAT domain of human C-P4H-II complexed with the intact beta/PDI-subunit, at 3.8A resolution. The CAT domain interacts with the a, b', and a' domains of the beta/PDI-subunit, such that the CAT active site is facing bulk solvent. The structure also shows that the C-P4H-II CAT domain has a unique N-terminal extension, consisting of alpha-helices and a beta-strand, which is the edge strand of its major antiparallel beta-sheet. This extra region of the CAT domain interacts tightly with the beta/PDI-subunit, showing that the CAT-PDI interface includes an inter-subunit disulfide bridge with the a' domain and tight hydrophobic interactions with the b' domain. Using this new structural information, the structure of the mature C-P4H-II alpha2beta2 tetramer is predicted. The model suggests that the CAT active site properties are modulated by alpha-helices of the N-terminal dimerization domains of both subunits of the alpha2-dimer.
Crystal structure of the collagen prolyl 4-hydroxylase (C-P4H) catalytic domain complexed with PDI: towards a model of the C-P4H alpha2beta2 tetramer.,Murthy AV, Sulu R, Lebedev A, Salo AM, Korhonen K, Venkatesan R, Tu H, Bergmann U, Janis J, Laitaoja M, Ruddock L, Myllyharju J, Koski MK, Wierenga RK J Biol Chem. 2022 Oct 17:102614. doi: 10.1016/j.jbc.2022.102614. PMID:36265586[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Murthy AV, Sulu R, Lebedev A, Salo AM, Korhonen K, Venkatesan R, Tu H, Bergmann U, Janis J, Laitaoja M, Ruddock L, Myllyharju J, Koski MK, Wierenga RK. Crystal structure of the collagen prolyl 4-hydroxylase (C-P4H) catalytic domain complexed with PDI: towards a model of the C-P4H alpha2beta2 tetramer. J Biol Chem. 2022 Oct 17:102614. doi: 10.1016/j.jbc.2022.102614. PMID:36265586 doi:http://dx.doi.org/10.1016/j.jbc.2022.102614
