3D Structure of Factor VIII

CPK Color Scheme
C O N P S



Human factor VIII is a glycoprotein found in blood plasma that plays a crucial role in blood clotting. Shown here is the C2 domain of the human factor VIII at 1.5 resolution. This particular protein is found circulating throughout the body in the blood, which enables it to provide clotting anywhere needed.

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First, lets look at how exactly factor VIII binds. The factor VIII structure consists of 19 -strands. (upward running strands are red, downward running strands are orange)

Two out of the three -hairpins along with another loop extend outside the main structure and are the primary regions used in membrane binding.

To spin the protein to get an even better look, click here

In order to fully see the structure of these regions click here to view a close up of these amino acids. These regions prove to be predominatly hydrophobic, along with flanking a pair of positively charged clefts (Pratt, 1999).

By clicking here it is easier to see the varying amino acids found in these regions; all of which are hydrophobic. (orange=valine, yellow=phenylalanine, red=methionine, green=leucine) For a more indepth look at the chemical make up and structure of these amino acids please visit the Side-by-Side Amino Acid Viewer.

Factor VIII uses this hydrophobicity produced by these 4 hydrophobic amino acids to bury these three regions into the phospholipid bilayer surface in order to bind.

Hemophilia A is a blood clotting disorder that arises when mutations in factor VIII occur. These specific mutations are not limited to the binding region, but occur in the residues forming the protein core, the hydrophobic surface, surface-exposed residues and a few other residues that appear to be structurally important (Pratt,1999).

By clicking here one is able to see where each of the individual point mutations take place through-out the molecule. (purple=sites associated with severe cases of hemophilia A, yellow=sites of mutations associated with mild to moderate cases)


References

Pratt, K.P., Shen, B.W., Takeshima, K., Davie, E.W., Fujikawa, K., and Stoddard, B.L. 1999. Structure of the C2 domain of human factor VIII at 1.5 resolution. Nature. 402:439-441.