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Crystal structure of the heterodimeric human C-P4H-II with truncated alpha subunit (C-P4H-II delta281)
Structural highlights
DiseaseP4HA2_HUMAN The disease is caused by mutations affecting the gene represented in this entry. FunctionP4HA2_HUMAN Catalyzes the post-translational formation of 4-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens and other proteins. Publication Abstract from PubMedCollagen 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
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