4bdw
From Proteopedia
The structure of the FnI-EGF tandem domain of coagulation factor XII in complex with Holmium
Structural highlights
Disease[FA12_HUMAN] Congenital factor XII deficiency;Hereditary angioedema type 3. Defects in F12 are the cause of factor XII deficiency (FA12D) [MIM:234000]; also known as Hageman factor deficiency. This trait is an asymptomatic anomaly of in vitro blood coagulation. Its diagnosis is based on finding a low plasma activity of the factor in coagulating assays. It is usually only accidentally discovered through pre-operative blood tests. F12 deficiency is divided into two categories, a cross-reacting material (CRM)-negative group (negative F12 antigen detection) and a CRM-positive group (positive F12 antigen detection).[1] [2] [3] [4] [5] [6] [7] [8] [9] Defects in F12 are the cause of hereditary angioedema type 3 (HAE3) [MIM:610618]; also known as estrogen-related HAE or hereditary angioneurotic edema with normal C1 inhibitor concentration and function. HAE is characterized by episodic local subcutaneous edema, and submucosal edema involving the upper respiratory and gastrointestinal tracts. HAE3 occurs exclusively in women and is precipitated or worsened by high estrogen levels (e.g. during pregnancy or treatment with oral contraceptives). It differs from HAE types 1 and 2 in that both concentration and function of C1 inhibitor are normal.[10] [11] Function[FA12_HUMAN] Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then trypsin cleaves it to beta-factor XIIa. Alpha-factor XIIa activates factor XI to factor XIa.[12] Publication Abstract from PubMedCoagulation factor XII (FXII) is a key protein in the intrinsic coagulation and kallikrein-kinin pathways. It has been found that negative surfaces and amyloids, such as Abeta fibrils, can activate FXII. Additionally, it has been suggested that FXII simulates cells and that it plays an important role in thrombosis. To date, no structural data on FXII have been deposited, which makes it difficult to support any hypothesis on the mechanism of FXII function. The crystal structure of the FnI-EGF-like tandem domain of FXII presented here was solved using experimental phases. To determine the phases, a SIRAS approach was used with a native and a holmium chloride-soaked data set. The holmium cluster was coordinated by the C-terminal tails of two symmetry-related molecules. Another observation was that the FnI domain was much more ordered than the EGF-like domain owing to crystal packing. Furthermore, the structure shows the same domain orientation as the homologous FnI-EGF-like tandem domain of tPA. The plausibility of several proposed interactions of these domains of FXII is discussed. Based on this FXII FnI-EGF-like structure, it could be possible that FXII binding to amyloid and negatively charged surfaces is mediated via this part of FXII. The structure of the FnI-EGF-like tandem domain of coagulation factor XII solved using SIRAS.,Beringer DX, Kroon-Batenburg LM Acta Crystallogr Sect F Struct Biol Cryst Commun. 2013 Feb 1;69(Pt 2):94-102., doi: 10.1107/S1744309113000286. Epub 2013 Jan 26. PMID:23385745[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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