8k0f

Human collagen prolyl processing enzyme complex, P3H1/CRTAP/PPIB heterotrimer, in its apo stateHuman collagen prolyl processing enzyme complex, P3H1/CRTAP/PPIB heterotrimer, in its apo state

Structural highlights

8k0f is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.37Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

P3H1_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]

Function

P3H1_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 PubMed

Collagen 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

↑ Willaert A, Malfait F, Symoens S, Gevaert K, Kayserili H, Megarbane A, Mortier G, Leroy JG, Coucke PJ, De Paepe A. Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation. J Med Genet. 2009 Apr;46(4):233-41. PMID:19088120 doi:10.1136/jmg.2008.062729
↑ Kaul SC, Sugihara T, Yoshida A, Nomura H, Wadhwa R. Gros1, a potential growth suppressor on chromosome 1: its identity to basement membrane-associated proteoglycan, leprecan. Oncogene. 2000 Jul 27;19(32):3576-83. PMID:10951563 doi:10.1038/sj.onc.1203696
↑ 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. The structural basis for the collagen processing by human P3H1/CRTAP/PPIB ternary complex. Nat Commun. 2024 Sep 8;15(1):7844. PMID:39245686 doi:10.1038/s41467-024-52321-6

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OCA

[1] Willaert A, Malfait F, Symoens S, Gevaert K, Kayserili H, Megarbane A, Mortier G, Leroy JG, Coucke PJ, De Paepe A. Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation. J Med Genet. 2009 Apr;46(4):233-41. PMID:19088120 doi:10.1136/jmg.2008.062729

[2] Kaul SC, Sugihara T, Yoshida A, Nomura H, Wadhwa R. Gros1, a potential growth suppressor on chromosome 1: its identity to basement membrane-associated proteoglycan, leprecan. Oncogene. 2000 Jul 27;19(32):3576-83. PMID:10951563 doi:10.1038/sj.onc.1203696

[3] 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. The structural basis for the collagen processing by human P3H1/CRTAP/PPIB ternary complex. Nat Commun. 2024 Sep 8;15(1):7844. PMID:39245686 doi:10.1038/s41467-024-52321-6

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