Official Full Name
Factor XI
Background
Factor XI is a plasma glycoprotein which circulates in a non-covalent complex with high molecular weight kininogen. The mature molecule is synthesized in the liver and is a two-chain homodimer with a molecular weight of approximately 160,000. It is estimated that 5% of the total mass is attributable to carbohydrate. The two identical monomers have molecular weights of 80,000, and are joined together by disulfide bonds. Thus by SDS-PAGE analysis, factor XI appears as a single band both non-reduced (Mr=160,000), and reduced (Mr=80,000).
Factor XI circulates as a zymogen and requires proteolytic activation to acquire serine protease activity. The conversion of factor XI to factor XIa is catalyzed by factor XIIa, and results in cleavage of the Arg369-Ile370 bond in each monomer. Factor XIa consists of two NH2-terminal derived heavy chains, and two COOH-terminal derived light chains, all of which are held together by disulfide bonds. Factor XIa participates within the intrinsic pathway of coagulation by catalyzing the conversion of factor IX to factor IXa. A bleeding disorder called plasma thromboplastin antecedent deficiency results from a lack of factor XI procoagulant activity. The variable bleeding tendencies observed in factor XI deficient patients do not correlate with either factor XI activity or antigen levels. This latter observation may be related to the ability of the tissue factor/factor VIIa complex to also activate factor IX to IXa.
Historically, factor XI has been difficult to purify due to its relatively low concentration in plasma, and its susceptibility to proteolysis. Factor XI is purified from fresh frozen plasma that is stabilized by added inhibitors. The plasma is first treated with BaCl2 to remove the vitamin K-dependent proteins, and factor XI is then isolated by affinity chromatography. A final chromatography step on heparin sepharose yields a homogeneous preparation of intact factor XI. The finished product is supplied in 50% (vol/vol) glycerol/H2O and should be stored at -20°C.
Synonyms
Human Factor XI; Factor XI
Factor XI, also known as plasma thromboplastin antecedent, is a crucial component of the coagulation cascade. As a zymogen, Factor XI circulates in an inactive form until triggered by vascular injury, where it plays a vital role in the amplification of the coagulation pathway. Understanding the structure, function, and regulatory mechanisms of Factor XI is essential for unraveling its significance in hemostasis and for developing novel therapeutic interventions in coagulation disorders.
Structure
Factor XI is a homodimeric glycoprotein composed of two identical subunits linked by disulfide bonds. Each subunit consists of several domains, including an N-terminal region, apple 1 domain, apple 2 domain, and a protease domain. The catalytic site responsible for enzymatic activity is located within the protease domain, where Factor XI undergoes activation through proteolytic cleavage.
Function
Factor XI serves as a critical component in the coagulation cascade, particularly in the intrinsic pathway. Upon activation by Factor XIIa or thrombin, Factor XI is converted into Factor XIa, a serine protease that cleaves Factor IX to initiate the activation of Factor X. This series of events lead to the generation of thrombin and the formation of a stable fibrin clot. Factor XI's position in the coagulation cascade highlights its role in thrombus formation and maintenance, crucial for hemostasis.
Mechanism
Factor XI activation occurs through proteolytic cleavage at specific sites within the zymogen. Upon activation by Factor XIIa or thrombin, Factor XIa exhibits enhanced catalytic activity and initiates the activation of downstream coagulation factors, culminating in thrombin generation and fibrin clot formation. The precise regulatory mechanisms governing Factor XI activation and inactivation are critical for maintaining hemostatic balance and preventing thrombosis.
Regulation
The regulation of Factor XI activity is finely tuned by various endogenous inhibitors, including antithrombin and tissue factor pathway inhibitor. Additionally, physiological activators and inhibitors modulate Factor XI activation and function in response to vascular injury and hemostatic challenges. Dysregulation of Factor XI activity has been implicated in thrombotic disorders, emphasizing the importance of understanding the intricate regulatory mechanisms that govern its function.
Applications
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Drug Development
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Computational modeling of Factor XI interactions with small molecules and inhibitors to design novel therapeutics for coagulation disorders.
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Virtual screening studies to identify lead compounds targeting Factor XI for the development of anticoagulant drugs with improved efficacy and safety profiles.
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Disease Mechanisms
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Investigating the role of Factor XI in thrombotic disorders, such as deep vein thrombosis and ischemic stroke, through computational simulations and molecular dynamics studies.
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Elucidating the molecular mechanisms underlying Factor XI deficiency or dysregulation in hemostatic disorders to guide targeted therapeutic interventions.
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Personalized Medicine
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Utilizing computational tools to predict individual responses to Factor XI-targeted therapies based on genetic variations and pharmacogenomic factors.
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Integrating structural bioinformatics approaches to optimize treatment strategies and dosing regimens for patients with Factor XI-related coagulation disorders.
Conclusion
Factor XI stands at the crossroads of coagulation, serving as a pivotal player in ensuring vascular integrity and hemostasis. Its intricate structure, function, mechanism of action, regulation, and diverse applications highlight the complexity underlying clot formation and resolution. By unraveling the mysteries of Factor XI, we not only enhance our understanding of hemostasis but also pave the way for novel therapeutic interventions and personalized treatments tailored to individual clotting profiles. Embracing the enigma of Factor XI opens doors to a deeper comprehension of the body's innate ability to maintain vascular equilibrium and respond to injury, showcasing the beauty and complexity of nature's design in sustaining life.
