What is the C1 Inhibitor Structure and Function Related Diseases C1 Inhibitor Test Drug Discovery
Among the critical regulators is C1 inhibitor (C1-INH), also known as SERPING1, a serine protease inhibitor (serpin) that plays a central role in controlling the classical and lectin pathways of the complement cascade. Understanding the molecular function, structure, and clinical relevance of C1-INH is essential for researchers investigating inflammation, autoimmunity, hereditary angioedema, and complement-targeted drug discovery.
Creative Biolabs offers a comprehensive suite of complement research solutions, including recombinant C1-INH protein production, SERPING1 gene analysis, functional assays, and therapeutic antibody development, to support basic and translational studies across immunology and biopharmaceutical fields.
What is the C1 Inhibitor?
C1-INH is a glycoprotein (~105 kDa) synthesized primarily by hepatocytes and circulating in plasma at a concentration of 0.2–0.3 mg/mL. It is a member of the serpin superfamily and inhibits several proteases involved in the complement, coagulation, fibrinolytic, and kallikrein-kinin systems.
Table 1 Core functions of C1 inhibitors.
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Pathway
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Protease Targets
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Functional Role of C1INH
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Classical complement pathway
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C1r, C1s
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Prevents spontaneous activation of C1 complex
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Lectin pathway
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MASP-1, MASP-2
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Inhibits lectin-triggered complement activation
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Kallikrein-kinin system
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Plasma kallikrein, Factor XIIa
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Regulates bradykinin production and vascular permeability
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Coagulation system
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FXIa, Thrombin (minor)
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Cross-regulates hemostasis and inflammation
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It plays a role in the regulation of the classical complement pathway, the contact activation system, and the intrinsic coagulation pathway. In addition to its ability to inhibit several proteases, C1-INH also exhibits a broad spectrum of non-inhibitory biological activity. Through the study of hereditary angioedema (HAE) caused by plasma functional C1-INH deficiency, C1-INH's role in regulating vascular permeability has been demonstrated. Subsequent research has gradually revealed the structure and biological activity of C1-INH, allowing us to make great progress in understanding its therapeutic potential and research and development based on C1-INH.
C1-INH Structure and Function
C1-INH consists of two major domains:
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N-terminal domain: Contains heavily glycosylated sites, contributing to its stability and plasma half-life.
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C-terminal serpin domain: Contains a reactive center loop (RCL) that acts as a pseudosubstrate for target proteases.
Fig. 1 Overall structure of the native C1-INH serpin domain, with crucial regions ascribed to C1-INH serpin function.1,2
Upon cleavage by a target protease, C1-INH forms a stable 1:1 inhibitory complex, inactivating the protease irreversibly. This mechanism is critical for timely regulation of inflammatory cascades and prevention of host damage.
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Structural characterization of C1-INH. C1-INH is a highly glycosylated protein, and the inherent heterogeneity of the carbohydrate portion greatly promotes the heterogeneity of the entire C1-INH. This may be one of the reasons why the natural glycosylated C1-INH crystal structure is still not available.
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Biosynthesis of C1-INH. Human C1-INH is encoded by the SERPING1 gene on chromosome 11, and is mainly synthesized and secreted by hepatocytes, but is also produced by monocytes, fibroblasts, macrophages, endothelial cells and other cells. C1-INH biosynthesis can be stimulated by cytokines, especially interferon-γ.
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Abundance of C1-INH. Human C1-INH is a forward acute phase plasma glycoprotein, and its concentration is normal in healthy subjects, about 240 µg / mL, but its level may increase 2-2.5 times during inflammation. Low C1-INH plasma levels or dysfunction can lead to activation of complement and exposure to the plasma cascade and may also affect other systems.
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Inhibition of proteases and other activities. C1-INH has the ability to inhibit several proteases and plays a role in the down-regulation of four major plasma cascade systems.
C1-INH Related Diseases
C1-INH deficiency—either quantitative (Type I) or functional (Type II)—leads to uncontrolled activation of the kallikrein-kinin pathway, resulting in elevated bradykinin and life-threatening angioedema attacks.
Table 2 HAE.
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HAE Type
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Cause
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C1-INH Status
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SERPING1 Mutation
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Type I
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Gene deletion/missense
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↓ Protein level
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Pathogenic
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Type II
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Functional defect
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Normal protein, ↓ activity
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Dominant-negative
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In certain lymphoproliferative or autoimmune diseases, autoantibodies or increased catabolism of C1-INH can mimic HAE symptoms, often referred to as acquired angioedema (AAE).
C1 inhibitor assays play a critical role in the study of diseases associated with disorders of the complement system. Accurate and comprehensive assays (from antigen level measurements to functional activity assays) are essential in a variety of research applications.
C1-INH tests refer to assays that evaluate the concentration and activity of C1 inhibitors in plasma or serum. These tests are primarily used to investigate complement-related immunodeficiencies.
Table 3 Key diagnostic parameters.
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Test Type
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Purpose
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Application
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C1-INH Protein Level (Quantitative)
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Measures circulating C1-INH protein
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Detects Type I HAE (low level)
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C1-INH Functional Activity
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Assesses ability to inhibit target proteases
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Detects Type II HAE (normal level, low activity)
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C4 Level
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Often used as a screening marker
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C4 is reduced in active disease
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SERPING1 Gene Analysis
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Identifies mutations causing C1-INH deficiency
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Confirms inherited vs. sporadic cases
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We support C1-INH-related research through validated assays:
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ELISA Kits: Quantification of plasma C1-INH levels
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Activity Assays: Inhibition of C1s, kallikrein, MASPs
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Western Blot & IHC: Protein expression in tissues
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Surface Plasmon Resonance (SPR): Protein-protein interaction kinetics
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Flow Cytometry: Immune cell activation status under C1-INH treatment
C1-INH Research in Drug Discovery
The complement system has emerged as a major druggable target in immune and inflammatory diseases, with C1-INH playing a pivotal role in its regulation. As a key endogenous controller of the classical and lectin pathways, C1-INH has become central to both mechanistic research and therapeutic intervention strategies.
C1-INH represents both a biomarker and a drug candidate in numerous disease contexts.
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HAE: Deficiency causes severe attacks
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Immuno-oncology: Complement shapes tumor microenvironment
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Transplant medicine: Regulates complement-mediated rejection
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Neuroinflammation: Inhibits complement in brain injury
We offer an end-to-end platform that supports every phase of C1-INH-centered R&D. Drug modalities targeting C1-INH include:
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Plasma-Derived and Recombinant C1-INH
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Gene Therapy
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Small Molecule Modulators
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Monoclonal Antibodies / Fc-Fusion Proteins
At Creative Biolabs, we integrate deep expertise in complement biology, protein engineering, and biologic drug development to empower your C1-INH research.
If you want more information, please feel free to contact us.
References
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Maia, Luana Sella Motta, et al. "Recessive SERPING1 Variant Leads to Kinin–Kallikrein System Control Failure in a Consanguineous Brazilian Family with Hereditary Angioedema." Journal of Clinical Medicine 12.23 (2023): 7299. https://doi.org/10.3390/jcm12237299
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Distributed under Open Access license CC BY 4.0, without modification.
For Research Use Only.
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