User:Natalie Mullins/Sandbox Wauwatosa West SMART Team
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Abstract
Fibrinogen (3ghg) is the precursor to fibrin, the last protein in the blood clotting process. Fibrin forms the clot that is stabilized by factor XIII (1f13), causing fibrin monomerss to link together. Without fibrin, a person would bleed to death. Fibrinogen is made up of three unique polypeptide chains: α, β, and γ. These chains are twisted together, forming two terminal barbell-like a smaller central in between. Thrombin, another essential clotting protein, forms fibrin by removing alpha and beta chain amino termini peptides in the E domain, exposing amino acid interact with depressions—“holes”—always present on D domains of neighboring molecules. Van der Waals forces keep the α and β chains together between the E and D domains. Cross-linking occurs between D domains of adjacent molecules at residues Gln398/399 of one D domain and Lys406 of the other. There is currently controversy within the scientific community over whether fibrin D domains cross-link longitudinally (end-to-end) or transversely (between parallel molecules). Cross-linking transversely allows for greater elasticity, allowing the clot to stretch with the skin or blood vessels. Studies with fibrinogen in physiological solution strongly suggest cross linking occurs in a transverse manner. Although the cross-linking residues (381-411) in the crystalline structure appear to be too short to link transversely, if the loop on the γ chain could flip out, it would provide an extension. Using 3D printer technology, the Wauwatosa West SMART Team (Students Modeling A Research Topic) designed a fibrinogen model to visualize this loop.
History
WWI surgeons created their own “homemade” pre- polymerized fibrin sheets and powders for use as homeostatic agents for battle field trauma to stop bleeding before it became fatal. During WWII these products were mass produced by the military and the American Red Cross. They were later withdrawn because they were capable of transmitting various diseases.It is important that fibrinogen is “stretchy” because it allows the fibrinogen to “move” with your body, preventing it from tearing. Without this feature fibrinogen would be constantly tearing in the active human body, exposing the person to continued blood loss.
Structure
Human fibrinogen is made up of three alpha helix chains: alpha, beta, and gamma. These chains are coiled around each other, forming two barbell-like D domains at both ends and a smaller E domain in the middle. On the D domain is a kind of loop structure, made up of amino acids, that flips out to form covalent bonds between neighboring fibrin molecules. It is these bonds that allow the fibrinogen to polymerize into a fibrin clot.
Cross-Linking
Before fibrinogen can form covalent bonds between neighboring molecules, it must first align with those molecules through Van der Waals forces. These forces become active when factor XIII cleaves peptide bonds on the fibrinogen molecule, making it into fibrin and exposing the "knobs" on the E domain. These knobs interact with the holes on the D domain through Van de Waals forces, allowing the fibrin monomers to align with each other. Another protein in the clotting process, thrombin (3u69), then comes in to form covalent bonds between the two loops on the d domain. There is current controversy in the scientific community on whether the fibrin monomers cross-link longitudinally, between congruent molecules, or transversely between parallel molecules. Those on the congruent side argue that the crystallized loop is not long enough to reach all the way across to a parallel molecule. This longitudinal cross-linking, however, would not explain why fibrin is so stretch as a clot, since the longitudinal covalent bonds would just break if they were pulled upon.
