This entry represents the membrane-proximal domain (MPD) of disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) from animals. ADAM17 is a major sheddase responsible for the regulation of a wide range of biological processes, such as cellular differentiation, regeneration, and cancer progression. This MPD region acts as the sheddase switch. PDI (protein-disulfide isomerase) interacts with ADAM17 and down-regulates its enzymatic activity. The interaction is directly with the MPD, the region of dimerisation and substrate recognition, where it catalyses an isomerisation of disulfide bridges within the thioredoxin motif CXXC. This isomerisation results in a major structural change between an active, open state and an inactive, closed state of the MPD. This change is thought to act as a molecular switch, allowing a global reorientation of the extracellular domains in ADAM17 and regulating its shedding activity [].
This entry includes proteins with reprolysin-like metallopeptidase domains and includes ADAM10 (also known as myelin-associated metalloendopeptidase, MEROPS identifier M12.210), ADAM17 (also known as tumour necrosis factor alpha-convertase, MEROPS identifier M12.217), kuzbanian (MEROPS identifiers M12.211 and M12.322) and ADM-4 (MEROPS identifier M12.329) [].
Proteins in this family include the envelope glycoprotein and the pre-small/secreted glycoprotein from Filoviridae []. The envelope glycoprotein can be cleaved into 3 chains: GP1, GP2 and GP2-delta.GP1 is responsible for binding to the receptor(s), such as CD209 and CLEC4M, on target cells. These interactions not only facilitate virus cell entry, but also allow capture of viral particles by dendritic cells (DCs) and subsequent transmission to susceptible cells without DCs infection (trans infection) [].GP2 acts as a class I viral fusion protein. It is responsible for penetration of the virus into the cell cytoplasm by mediating the fusion of the membrane of the endocytosed virus particle with the endosomal membrane []. GP1,2 peplomers mediates endothelial cell activation and decreases endothelial barrier function. It mediates activation of primary macrophages. At terminal stages of the viral infection, when its expression is high, GP1,2 down-modulates the expression of various host cell surface molecules that are essential for immune surveillance and cell adhesion [].GP2delta is part of the complex GP1,2delta released by host ADAM17 metalloprotease. This secreted complex may play a role in the pathogenesis of the virus by efficiently blocking the neutralizing antibodies that would otherwise neutralize the virus surface glycoproteins GP1,2. Might therefore contribute to the lack of inflammatory reaction seen during infection in spite the of extensive necrosis and massive virus production. GP1,2delta does not seem to be involved in activation of primary macrophage [].pre-small/secreted glycoprotein sGP seems to possess an anti-inflammatory activity as it can reverse the barrier-decreasing effects of TNF alpha. It might therefore contribute to the lack of inflammatory reaction seen during infection in spite the of extensive necrosis and massive virus production. It does not seem to be involved in activation of primary macrophages. It does not seem to interact specifically with neutrophils [, , , ].
