CRTAP Human
Description
Molecular Structure and Function
CRTAP forms a ternary complex with prolyl 3-hydroxylase 1 (P3H1) and cyclophilin B (PPIB), termed the prolyl 3-hydroxylation complex (PCP). This complex facilitates collagen post-translational modification, specifically 3-hydroxylation of Pro986 in collagen α-chains . Key structural insights include:
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X-shaped base architecture: CRTAP and P3H1’s N-terminal domains form a pseudosymmetric scaffold, while PPIB binds asymmetrically to stabilize collagen interactions .
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Collagen-binding role: CRTAP directly anchors collagen substrates, enabling P3H1 enzymatic activity .
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Mutual stabilization: CRTAP and P3H1 depend on each other for stability; loss of either component disrupts the complex and collagen modification .
Genetic Mutations and Pathogenesis
Over 80 pathogenic variants in CRTAP are documented, primarily causing autosomal recessive osteogenesis imperfecta (OI types VII and IIB) . Notable findings:
Mutation Types and Effects
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Compound heterozygosity: A patient with a paternal splicing mutation (c.1153-3C>G) and maternal 1.81 Mb deletion exhibited severe OI due to near-complete loss of CRTAP mRNA .
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Conservation and pathogenicity: The c.1153-3C>G variant disrupts a highly conserved splice site (phastCons score: 0.911) and is classified as pathogenic per ACMG guidelines .
Osteogenesis Imperfecta (OI)
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Severe phenotypes: Perinatal fractures, rhizomelia, kyphosis, and progressive skeletal deformities .
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Collagen abnormalities: Loss of CRTAP reduces 3-hydroxylation of collagen Pro986, increasing helical overmodification (e.g., lysyl hydroxylation) and disrupting fibril assembly .
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Therapeutic response: Bisphosphonates (e.g., pamidronate) improve mobility in hypomorphic cases but show limited efficacy in null mutations .
Non-Skeletal Manifestations
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Cardiac defects: Mitral regurgitation reported in a sibling case .
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Respiratory compromise: Thoracic cage deformities and potential direct lung involvement contribute to infant mortality in severe OI .
Research Advances
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CRTAP-P3H1 interaction: Cryo-EM revealed the PCP complex’s collagen-binding zone, explaining how CRTAP mutations impair substrate recruitment .
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Mouse models: Crtap⁻/⁻ mice exhibit tendon hyper-crosslinking and motor deficits, mirroring human OI tendon pathology .
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Population genetics: Rare CRTAP alleles (MAF: 0.1% in Taiwanese) highlight the need for expanded carrier screening to prevent autosomal recessive OI .
Diagnostic and Therapeutic Outlook
Product Specs
Product Science Overview
Ucma was discovered as a protein highly expressed in the articular cartilage and osteophytes during arthritis. It has been identified as a key player in blocking the activity of ADAMTS aggrecanases, enzymes that contribute to cartilage degeneration. The ability of Ucma to inhibit these enzymes makes it a promising target for therapeutic interventions aimed at preventing cartilage degradation in conditions such as osteoarthritis and rheumatoid arthritis .
Ucma exerts its protective effects on cartilage by physically interacting with ADAMTS5, one of the major aggrecanases involved in cartilage breakdown. This interaction inhibits the aggrecanase activity of ADAMTS5, thereby preventing the degradation of aggrecan, a critical component of the cartilage extracellular matrix. Studies have shown that Ucma can effectively inhibit ADAMTS5-triggered or IL-1β-triggered aggrecanolysis both in vitro and in vivo .
The therapeutic potential of Ucma lies in its ability to protect cartilage from degradation in inflammatory arthritis. Experimental studies have demonstrated that treatment with recombinant Ucma can inhibit cartilage degeneration and reduce osteophyte formation in animal models of arthritis. This suggests that Ucma could be developed as a novel therapeutic agent for preventing cartilage degradation and promoting cartilage repair in patients with arthritis .
