8k17
Human collagen prolyl processing enzyme complex, P3H1/CRTAP/PPIB heterotrimer, bound to collagen alpha-1(I) chain
Structural highlights
DiseaseP3H1_HUMAN Osteogenesis imperfecta type 2;Osteogenesis imperfecta type 3. The disease is caused by variants affecting the gene represented in this entry. A splice site mutation leading to the absence of isoform 1 has been reported in 2 OI8 patients. Isoform 1 is the only form predicted to be located in the endoplasmic reticulum, which the appropriate location for the catalysis of collagen hydroxylation. These patients show indeed severely reduced COL1A1 hydroxylation (PubMed:19088120).[1] FunctionP3H1_HUMAN Basement membrane-associated chondroitin sulfate proteoglycan (CSPG). Has prolyl 3-hydroxylase activity catalyzing the post-translational formation of 3-hydroxyproline in -Xaa-Pro-Gly- sequences in collagens, especially types IV and V. May be involved in the secretory pathway of cells. Has growth suppressive activity in fibroblasts.[2] Publication Abstract from PubMedCollagen posttranslational processing is crucial for its proper assembly and function. Disruption of collagen processing leads to tissue development and structure disorders like osteogenesis imperfecta (OI). OI-related collagen processing machinery includes prolyl 3-hydroxylase 1 (P3H1), peptidyl-prolyl cis-trans isomerase B (PPIB), and cartilage-associated protein (CRTAP), with their structural organization and mechanism unclear. We determine cryo-EM structures of the P3H1/CRTAP/PPIB complex. The active sites of P3H1 and PPIB form a face-to-face bifunctional reaction center, indicating a coupled modification mechanism. The structure of the P3H1/CRTAP/PPIB/collagen peptide complex reveals multiple binding sites, suggesting a substrate interacting zone. Unexpectedly, a dual-ternary complex is observed, and the balance between ternary and dual-ternary states can be altered by mutations in the P3H1/PPIB active site and the addition of PPIB inhibitors. These findings provide insights into the structural basis of collagen processing by P3H1/CRTAP/PPIB and the molecular pathology of collagen-related disorders. The structural basis for the collagen processing by human P3H1/CRTAP/PPIB ternary complex.,Li W, Peng J, Yao D, Rao B, Xia Y, Wang Q, Li S, Cao M, Shen Y, Ma P, Liao R, Qin A, Zhao J, Cao Y Nat Commun. 2024 Sep 8;15(1):7844. doi: 10.1038/s41467-024-52321-6. PMID:39245686[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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