The structure of the FnI-EGF-like tandem domain of coagulation factor XII solved using SIRAS

Abstract

Coagulation 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 A 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 symmetryrelated 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-EGFlike 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.

Model for surface-dependent factor XII activation: the roles of factor XII heavy chain domains

“…Indeed, each FXII domain has been implicated by at least one study. 12,18,[34][35][36]38,[39][40][41] Our data indicate that EGF1 is central to polyanionic surface-binding during FXII autoactivation and FXIIa activation of PK. The strong positive charge on EGF1 is consistent with this role.…”

Molecular Characterization of Cat Factor XII Gene and Identification of a Mutation Causing Factor XII Deficiency in a Domestic Shorthair Cat Colony

“…In humans, the heavy chain has high homology with urokinase and tissue plasminogen activator, 6 along with type II fibronectin regions, which may contribute to FXII's binding to cellular surfaces and collagen. 2,36 We evaluated whether prekallikrein activation to kallikrein was altered in our cat colony via plasma mixing studies. By using prekallikreindeficient human plasma mixed with mutant cat plasma (suspected to be FXII deficient), we were able to test whether cat kallikrein could activate human high molecular weight kininogen (HK) and ultimately human FXI.…”

“…27 Fibronectin type I and II domains can bind extracellular matrix proteins and are thought to be involved in the cell-mediated binding of FXIIa. 2,6,36 In humans, congenital FXII deficiency is caused by a variety of genetic defects that result mostly in a loss of functional and identifiable FXII protein. The most common defect is a single 46 ''c'' to ''t'' (46C>T) nucleotide substitution in the promoter region of exon 1 on 1 allele (heterozygous) or both alleles (homozygous).…”

Heparan Sulfate Proteoglycans Mediate Factor XIIa Binding to the Cell Surface

“…Moreover, structural studies on factor IX or factor X indicate that these proteins interact with heparin via positively charged surfaces homologous to the heparin binding site described in thrombin (28,29). Interestingly, the study of FXII architecture reveals the presence of an electropositive path on the protein surface formed by the fibronectin type II domain and the epidermal growth factorlike region on the protein N terminus (30). Because similar structures were found to mediate the binding of various coagulation factors to heparin, it is tempting to speculate that this electropositive area may mediate FXIIa interaction with HStype GAGs.…”