Platelet Aggregation (Plug Formation) (Homo sapiens)
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Description
The tethering of platelets to the site of vascular injury is the first step in the formation of a platelet thrombus. Firm adhesion of these tethered platelets, as well as the additional recruitment of others onto their surface leads to the formation of large platelet aggregates. The formation of a thrombus is strictly dependent on the formation of interplatelet bonds.
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complex:activated thrombin (factor
IIa)In this pathway, we describe signaling through integrin alphaIIb beta3 as a representative example.
At the sites of vascular injury bioactive molecules such as thrombin, ADP, collagen, fibrinogen and thrombospondin are generated, secreted or exposed. These stimuli activate platelets, converting the major platelet integrin alphaIIbbeta3 from a resting state to an active conformation, in a process termed integrin priming or 'inside-out signalling'. Integrin activation refers to the change required to enhance ligand-binding activity. The activated alphaIIbbeta3 interacts with the fibrinogen and links platelets together in an aggregate to form a platelet plug. AlphaIIbbeta3 bound to fibrin generates more intracellular signals (outside-in signalling), causing further platelet activation and platelet-plug retraction.
In the resting state the alpha and beta tails are close together. This interaction keeps the membrane proximal regions in a bent conformation that maintains alphaIIbbeta3 in a low affinity state.
Integrin alphaIIbbeta3 is released from its inactive state by interaction with the protein talin. Talin interacts with the beta3 cytoplasmic domain and disrupts the salt bridge between the alpha and beta chains. This separation in the cytoplasmic regions triggers the conformational change in the extracellular domain that increases its affinity to fibrinogen.
Much of talin exists in an inactive cytosolic pool, and the Rap1 interacting adaptor molecule (RIAM) is implicated in talin activation and translocation to beta3 integrin cytoplasmic domain.
Annotated Interactions
complex:activated thrombin (factor
IIa)