Fibrinogen is a protein produced by the liver that circulates in blood plasma. It serves as the primary material for blood clots, which stop bleeding when a blood vessel is injured. This protein remains inactive in the bloodstream until a specific signal initiates the clotting process. Once activated, it converts into a sturdy, mesh-like structure that forms the backbone of a clot, sealing the injury so healing can begin.
The Polypeptide Chain Composition
Every fibrinogen molecule is a large, complex glycoprotein, classified as a hexamer because it is constructed from six polypeptide chains. These chains come in three pairs: two Aα, two Bβ, and two γ. The assembly of these chains into a single functional unit occurs within liver cells. The chains are intricately linked by 29 disulfide bridges, which are strong chemical bonds that maintain the protein’s specific shape.
This arrangement begins with forming smaller Aα-γ and Bβ-γ complexes. These pairs then combine to form two half-molecules, each containing one of each type of chain. The final step is joining these two half-molecules to create the complete fibrinogen molecule. This composition is fundamental to the protein’s function in hemostasis.
The Three-Dimensional Assembly
The assembled fibrinogen molecule has an elongated shape described as trinodular, resembling a dumbbell. This structure is approximately 45 nanometers long and consists of three main globular domains. The central E domain serves as the hub connecting the two outer D domains. The connections are formed by long, thin segments known as coiled-coil regions.
The N-termini of all six polypeptide chains meet within the central E domain. From this point, the chains extend outwards, and the C-termini of the Bβ and γ chains fold to form the D domains at each end. The Aα chains are the longest; a portion of each extends into a flexible segment ending in a globular region called the αC domain. This symmetrical architecture is directly related to how fibrinogen molecules link together.
Structural Conversion to Fibrin
The conversion of soluble fibrinogen into insoluble fibrin is a final step of the coagulation cascade. This transformation is initiated by the enzyme thrombin, which targets the central E domain of the fibrinogen molecule. Thrombin cleaves small peptides from the Aα and Bβ chains, known as fibrinopeptide A (FPA) and fibrinopeptide B (FPB). Removing these fibrinopeptides uncovers previously hidden binding sites on the E domain.
Once these new sites, called “knobs,” are exposed on the central domain, they bind to complementary “holes” that are always present on the D domains of adjacent molecules. This interaction triggers a process called polymerization. Fibrinogen molecules begin linking end-to-middle, forming long, double-stranded chains called protofibrils. These protofibrils then aggregate laterally, creating the branching, mesh-like network of a soft fibrin clot.
Consequences of Structural Defects
Genetic mutations that alter the amino acid sequence of fibrinogen’s polypeptide chains can result in a condition called dysfibrinogenemia. In this disorder, the body produces structurally abnormal fibrinogen that does not function correctly. This can lead to either excessive bleeding from weak clots or inappropriate clotting (thrombosis). The protein’s precise structure is directly tied to its function.
For instance, a mutation in a D domain could prevent the binding required for polymerization, making it difficult to form stable fibrin fibers. A mutation affecting the central E domain might hinder thrombin’s ability to cleave the fibrinopeptides, delaying clot formation. These examples show how minor changes to the protein’s shape can disrupt hemostasis.