Proteolytic processing of platelet receptors

Figure 1. Platelet adhesion/signaling receptors and their ligands. Platelet glycoproteins GPIbα and GPVI can bind a variety of ligands, many of which trigger intracellular signals that lead to platelet activation, degranulation and increased affinity of αIIbβ3 for fibrinogen. Cytoskeletal proteins and 14‐3‐3ζ associate with the cytoplasmic tails of the GPIb‐IX‐V complex. GPIb‐IX‐V contains intersubunit and intrasubunit disulphide bonds, represented by S, symbolising the link between adjacent sulfhydryl moieties in GPIbα and between GPIbα and GPIbβ. Calmodulin (CAM) associates with the juxtamembrane cytoplasmic regions of GPIbβ, GPV, and GPVI. The penultimate residue of GPVI is cysteine, represented by a free sulfhydryl group, SH. Not all cytoplasmic components known to associate with cytoplasmic tails of each receptor are shown

Figure 2. Ectodomains of GPIbα, GPV, and GPVI are shed under conditions of platelet activation. Calmodulin dissociation from the juxtamembrane cytoplasmic region of GPIbβ, GPV and GPVI is a common event also observed in metalloproteolytic shedding of a number of cell receptor ectodomains across vascular biology. GPIbα and GPIbβ intersubunit disulphide bonds which remain intact after shedding of the glycocalicin ectodomain are represented as S symbols

Figure 3. Domain structure of ADAMs. (A) ADAMs have a uniform domain structure with a prodomain that is removed prior to transport to the cell membrane, followed by a metalloproteinase, disintegrin,cysteine‐rich and epidermal growth factor‐like domains domains, a transmembrane domains and a cytoplasmic tail. ADAM10 and ADAM17 do not have EGF‐like domains and do have a free sulfhydryl (SH) group within the prodomain which may coordinate with the HEHH Zn2+ binding sequence within the metalloproteinase domain. (B) Analysis of the crystal structure of human ADAM10 [76] suggests a closed conformation of the enzyme under resting conditions where the cysteine‐rich domain occludes the metalloproteinase active site. Under conditions of activation, the metalloproteinase domain is freed and a substrate can gain access to the catalytic site

Figure 4. Extracellular proteolysis controls the active levels of a range of growth factors, chemokines and adhesion receptors. Levels of a range of active biological compounds are controlled by the action of members of the ADAMs family of metalloproteinases. Only a selection of these proteins are shown here. These bioactive proteins cooperate and influence a broad spectrum of critical biological processes. EGFR, epidermal growth factor receptor; GP glycoprotein; ICAM, intercellular adhesion molecule; IL, interleukin; TGF, transforming growth factor; TNF, tissue necrosis factor