PSYCH 1XX3 Lecture Notes - Lecture 12: Acute-Phase Protein, Endothelium, Ceruloplasmin
19 May 2018
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1. F5 & F8 have similar domain structures and similar physiological roles
F5 physiology
• Synthesised only in hepatocytes
• Plasma F5 is taken up (not synthesised) by platelets, where they are stored in a partially
active form that confers some APC resistance in platelet granules.
• Circulates as a single chain molecule
• Binds to and stimulates TFPI
• Acts as the cofactor for F10 within the
prothrombinase complex
F8 physiology
• Synthesised in hepatocytes and in some
groups of endothelial cells
• It is stored with vWF in WPBs in
endothelial cells and circulates as a
heterodimer in a complex with vWF in
plasma
o vWF increases its t1/2, protects it
from APC and prevents premature
association with F10
o removal of vWF leads to change in
conformation and circulation as an
unstable heterotrimer
• circulating levels vary considerably
because F8 is an acute phase protein
• acts as the cofactor for F9 within the
intrinsic tenase complex
F5/F8 have homologous domain structures
• The common template is A1-A2-B-A3-C1-C2
o This domain sequence is also homologous to ceruloplasmin and hephastin
• A domains are responsible for inter-protein interactions
• C domains are responsible for phospholipid binding
• B domains have very low sequence similarity between F5 & F8 and play different roles
between the two
• F8 has additional acidic peptides which are responsible for its additional functions eg a3
binds vWF
2. The B domain is a key difference in the structure/function relationships between F5/F8
The F8 B domain is important for intracellular trafficking but NOT coagulation
• B domain allows F8 to bind to chaperone proteins within the ER
• Examples of such chaperone proteins are CNX/CRt and LMAN1/LMAN2; chaperone proteins
facilitate folding, quality control etc for transport into the Golgi and, ultimately, secretion
• Removal of B domain does not alter F8 half life/ cofactor activity and hence has no role in
pro-coagulant function
• Thrombin cleaves the B domain as well as the bond between A1/A2 to activate F8
The F5 B domain is important for coagulation
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