ADAMTS13 - ADAM metallopeptidase with thrombospondin type 1 motif 13 | Elisa - Clia - Antibody - Protein

Background

ADAMTS13 (ADAM metallopeptidase with thrombospondin type 1 motif 13) is a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. ADAMTS13 contains multiple domains, including a signal peptide, a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and multiple thrombospondin type 1 (TSP1) motifs. ADAMTS13 is primarily known for its role in cleaving VWF. VWF normally forms long multimeric strands, which are essential for platelet adhesion and aggregation during clot formation. However, excessively large VWF multimers can lead to thrombotic disorders. ADAMTS13 cleaves these large VWF multimers into smaller, less active forms, thereby regulating platelet aggregation and preventing excessive clot formation. Deficiency or dysfunction of ADAMTS13 can result in a rare but severe condition called thrombotic thrombocytopenic purpura (TTP). In TTP, the lack of functional ADAMTS13 leads to the buildup of large VWF multimers, which can cause widespread microvascular thrombosis and thrombocytopenia. ADAMTS13 may also have other physiological functions that are not fully understood. Some studies suggest potential involvement in angiogenesis, inflammation, and tissue remodeling. Autoantibodies inhibit ADAMTS13 activity, while in hereditary TTP, genetic mutations affect the production or function of ADAMTS13. Both conditions lead to the accumulation of large VWF multimers, resulting in microvascular thrombosis and associated complications. ADAMTS13 activity has also been implicated in other thrombotic disorders, such as arterial thrombosis and stroke.

Protein Structure

ADAMTS13 has a complex multi-domain structure characteristic of the ADAMTS family:

• Signal Peptide: Directs the nascent protein to the secretory pathway.
• Propeptide Domain: Maintains the enzyme in an inactive form until it is cleaved to activate the enzyme.
• Metalloprotease Domain: Contains the catalytic site with a zinc-binding motif essential for its proteolytic activity.
• Disintegrin-Like Domain: Facilitates interactions with other proteins and cellular components.
• Thrombospondin Type 1 Repeats (TSP1): ADAMTS13 has eight TSP1 repeats involved in binding to vWF and other ECM components.
• Cysteine-Rich Domain: Contributes to the protein’s stability and interactions.
• Spacer Domain: Connects other domains and influences substrate specificity and binding.
• CUB Domains: Two CUB (complement components C1r/C1s, Uegf, and Bmp1) domains are involved in binding to vWF.

Classification and Subtypes

ADAMTS13 is part of the ADAMTS family, which includes multiple members characterized by their TSP1 motifs and metalloprotease domains. While there are no subtypes of ADAMTS13, its unique function in cleaving vWF distinguishes it from other ADAMTS proteins.

Function and Biological Significance

ADAMTS13 plays a critical role in hemostasis by regulating the size of vWF multimers:

1. Cleavage of von Willebrand Factor: The primary function of ADAMTS13 is to cleave large vWF multimers into smaller, less active forms. This prevents the formation of excessive or abnormal blood clots.
2. Regulation of Blood Flow: By processing vWF, ADAMTS13 ensures normal blood flow, particularly in the microvasculature.
3. Prevention of Thrombotic Events: Proper function of ADAMTS13 prevents conditions such as thrombotic thrombocytopenic purpura (TTP), characterized by microvascular thrombosis, hemolytic anemia, and thrombocytopenia.

Interactions

ADAMTS13 interacts primarily with von Willebrand factor, but it may also interact with other proteins and components in the blood and ECM:

1. von Willebrand Factor: Cleaves vWF at specific sites to regulate its multimeric size and activity.
2. Integrins: The disintegrin-like domain facilitates interactions with integrins, which may influence cellular adhesion and signaling.
3. Other ECM Proteins: Although its primary substrate is vWF, ADAMTS13 may interact with other ECM components during tissue remodeling or repair processes.

Clinical Significance

ADAMTS13 has significant clinical implications, particularly related to hemostasis and thrombotic disorders:

1. Thrombotic Thrombocytopenic Purpura (TTP): A deficiency in ADAMTS13 activity, either congenital or acquired, leads to TTP, a life-threatening condition characterized by widespread microvascular thrombosis. Symptoms include hemolytic anemia, thrombocytopenia, renal dysfunction, neurological symptoms, and fever.
2. Disseminated Intravascular Coagulation (DIC): Altered ADAMTS13 activity may contribute to the pathogenesis of DIC, a condition involving widespread activation of the coagulation cascade and formation of microthrombi.
3. Stroke and Cardiovascular Diseases: Reduced ADAMTS13 activity has been linked to an increased risk of stroke and other cardiovascular diseases due to its role in regulating blood clot formation.
4. Pregnancy Complications: Altered ADAMTS13 levels are associated with pregnancy-related complications such as preeclampsia and HELLP syndrome (Hemolysis, Elevated Liver enzymes, and Low Platelets).

Summary

ADAMTS13 is a crucial enzyme in the ADAMTS family, responsible for the regulation of von Willebrand factor, a key player in blood coagulation. Its multi-domain structure allows it to interact specifically with vWF, cleaving it to prevent abnormal clot formation. Deficiency or dysfunction of ADAMTS13 leads to thrombotic thrombocytopenic purpura (TTP) and has implications in other thrombotic and cardiovascular diseases. Understanding ADAMTS13's structure, functions, interactions, and clinical significance provides valuable insights into its roles in maintaining normal hemostasis and preventing thrombotic disorders.