6tp5
From Proteopedia
Crystal structure of human Transmembrane prolyl 4-hydroxylase
Structural highlights
DiseaseP4HTM_HUMAN The disease is caused by mutations affecting the gene represented in this entry. FunctionP4HTM_HUMAN Catalyzes the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates HIF1A at 'Pro-402' and 'Pro-564'. May function as a cellular oxygen sensor and, under normoxic conditions, may target HIF through the hydroxylation for proteasomal degradation via the von Hippel-Lindau ubiquitination complex.[1] Publication Abstract from PubMedProlyl 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 (ER)-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 Ca2+-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 Ca2+-binding is relevant to the catalytic activity. Functional analysis demonstrated that Ca2+-binding affinity of P4H-TM is within the range of physiological Ca2+ concentration in the ER. P4H-TM was found both as a monomer and a dimer in solution, but the monomer-dimer equilibrium was not regulated by Ca2+. The catalytic site contained bound Fe2+ and N-oxalylglycine, which is an analogue of the cosubstrate 2-oxoglutarate. Comparison to 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 an unique EF-domain. Structure of transmembrane prolyl 4-hydroxylase reveals unique organization of EF and dioxygenase domains.,Myllykoski M, Sutinen A, Koski MK, Kallio JP, Raasakka A, Myllyharju J, Wierenga RK, Koivunen P J Biol Chem. 2020 Dec 17. pii: RA120.016542. doi: 10.1074/jbc.RA120.016542. PMID:33334883[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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