ABSTRACT
COVID-19, the respiratory infection caused by the novel coronavirus SARS-CoV-2, presents a clinical picture consistent with the dysregulation of many of the pathways mediated by the metalloprotease ADAM17. ADAM17 is a sheddase that plays a key role in the modulation of ACE2, the receptor which also functions as the point of attachment leading to cell entry by the virus. This work investigates the possibility that ADAM17 dysregulation and attachment of the SARS-CoV-2 virion to the ACE2 receptor are linked events, with the latter causing the former. Tetraspanins, the transmembrane proteins that function as scaffolds for the construction of viral entry platforms, are mooted as key components in this connection.
Subject(s)
ADAM17 Protein/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Receptors, Virus/metabolism , SARS-CoV-2/metabolism , Tetraspanin 29/metabolism , Virus Internalization , ADAM17 Protein/chemistry , Angiotensin-Converting Enzyme 2/chemistry , Binding Sites , COVID-19/epidemiology , COVID-19/transmission , COVID-19/virology , Humans , Models, Biological , Molecular Docking Simulation , Multiprotein Complexes/chemistry , Multiprotein Complexes/metabolism , Pandemics , Protein Binding , Protein Domains , Receptors, Virus/chemistry , SARS-CoV-2/physiology , Tetraspanin 29/chemistryABSTRACT
The angiotensin Converting Enzyme 2 (ACE2) receptor is a key component of the renin-angiotensin-aldesterone system (RAAS) that mediates numerous effects in the cardiovascular system. It is also the cellular point of contact for the coronavirus spike protein. Cleavage of the receptor is both important to its physiological function as well as being necessary for cell entry by the virus. Shedding of ACE2 by the metalloprotease ADAM17 releases a catalytically active soluble form of ACE2, but cleavage by the serine protease TMPRSS2 is necessary for virion internalization. Complicating the issue is the observation that circulating ACE2 can also bind to the virus effectively blocking attachment to the membrane-bound receptor. This work investigates the possibility that the inflammatory response to coronavirus infection can abrogate shedding by ADAM17, thereby favoring cleavage by TMPRSS2 and thus cell entry by the virion.