Reactome | factor IX -> factor IXa + factor IX activation peptide (factor XIa catalyst)

factor IX -> factor IXa + factor IX activation peptide (factor XIa catalyst)

Stable Identifier

R-HSA-158333

Type

Reaction [transition]

Species

Homo sapiens

Compartment

extracellular region, plasma membrane

Synonyms

activation of factor IX (factor XIa catalyst)

ReviewStatus

5/5

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factor IX -> factor IXa + factor IX activation peptide (factor XIa catalyst)

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The mature factor IX (FIX) is secreted and circulates in the plasma as an inactive 57kDa zymogen form F9(47-461). Activation of FIX involves cleavage of two peptide bonds, at arginine 191 (R191-A192, the α-cleavage) and at arginine 226 (R226-V227, the β-cleavage), releasing an activation peptide (A192-R226) (Di Scipio RG et al. 1978; Zögg T & Brandstetter H 2009). The activation peptide has no known function. This calcium-dependent reaction is catalyzed by factor XIa (FXIa), bound to platelet glycoprotein (GP) Ib:IX:V on the platelet cell surface (Osterud B et al. 1978; Gailani D et al. 2001; Geng Y et al. 2012). Binding studies showed that FIX does not bind to FXIa in the absence of calcium (Geng Y et al. 2012). Structural studies suggest that both activation of factor XI and binding it to FIX induced conformational changes at the interface between the catalytic and the apple domains of the activated FXIa. The conformational changes of FXIa increased the accessibility to the apple 3 (A3) domain to enable FIX binding (Geng Y et al. 2012; Bar Barroeta A et al. 2019). FIX activation is ordered. FIX first binds to the FXIa A3 domain followed by engagement at the protease active site and cleavage of the R191-Al192 bond (Geng Y et al. 2012, 2013; Gailani D et al. 2014). The cleavage after R191 facilitates cleavage of the R226-V227 bond, forming the activated FIXa (also known as factor IXaβ). Catalytic efficiency for the second cleavage by FXIa is 7-fold greater than for the first cleavage, explaining the low accumulation of the α-cleavage product of FIX (Wolberg AS et al. 1997; Smith SB et al. 2008; Geng Y et al. 2012; Mohammed BM et al. 2018). Activated FIXa comprises an N-terminal light chain and a C-terminal heavy chain held together by a disulphide bridge between cysteine resides 178 and 335 (Di Scipio RG et al. 1978; Zögg T & Brandstetter H 2009). X-ray structure of the FIXa EGF2/protease domain at 1.37 A revealed that a Na+-binding site in association with Ca2+-binding site contributed to stabilization of the FIXa protease domain (Vadivel K et al. 2019).

Literature References

PubMed ID	Title	Journal	Year
29223926	An update on factor XI structure and function Cheng, Q, Li, C, Emsley, J, Verhamme, IM, Ivanov, I, Matafonov, A, Dickeson, SK, Sun, MF, Gailani, D, Sun, D, Mohammed, BM	Thromb. Res.	2018
11342438	Model for a factor IX activation complex on blood platelets: dimeric conformation of factor XIa is essential Cheng, Q, Ho, D, Sun, MF, Walsh, PN, Gailani, D	Blood	2001
22961984	A sequential mechanism for exosite-mediated factor IX activation by factor XIa Bajaj, SP, Verhamme, IM, Messer, A, Smith, SB, Sun, MF, Geng, Y, Gailani, D	J. Biol. Chem.	2012