About: Functional analysis of potential cleavage sites in the MERS-coronavirus spike protein

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About: Functional analysis of potential cleavage sites in the MERS-coronavirus spike protein Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Functional analysis of potential cleavage sites in the MERS-coronavirus spike protein
Creator	Pöhlmann, Stefan Hoffmann, Markus Kleine-Weber, Hannah Elzayat, Mahmoud
Source	Medline; PMC
abstract	The Middle East respiratory syndrome-related coronavirus (MERS-CoV) can cause severe disease and has pandemic potential. Therefore, development of antiviral strategies is an important task. The activation of the viral spike protein (S) by host cell proteases is essential for viral infectivity and the responsible enzymes are potential therapeutic targets. The cellular proteases furin, cathepsin L and TMPRSS2 can activate MERS-S and may cleave the S protein at two distinct sites, termed S1/S2 and S2′. Moreover, a potential cathepsin L cleavage site in MERS-S has been reported. However, the relative importance of these sites for MERS-S activation is incompletely understood. Here, we used mutagenic analysis and MERS-S-bearing vectors to study the contribution of specific cleavage sites to S protein-driven entry. We found that an intact S1/S2 site was only required for efficient entry into cells expressing endogenous TMPRSS2. In keeping with a previous study, pre-cleavage at the S1/S2 motif (RSVR) was important although not essential for subsequent MERS-S activation by TMPRSS2, and indirect evidence was obtained that this motif is processed by a protease depending on an intact RXXR motif, most likely furin. In contrast, the S2′ site (RSAR) was required for robust viral entry into all cell lines tested and the integrity of one of the two arginines was sufficient for efficient entry. These findings suggest that cleavage at S2′ is carried out by proteases recognizing a single arginine, most likely TMPRSS2 and cathepsin L. Finally, mutation of the proposed cathepsin L site did not impact viral entry and double mutation of S1/S2 and S2′ site was compatible with cathepsin L- but not TMPRSS2-dependent host cell entry, indicating that cathepsin L can process the S protein at auxiliary sites. Collectively, our results indicate a rigid sequence requirement for S protein activation by TMPRSS2 but not cathepsin L.
has issue date	2018-11-09(xsd:dateTime)
bibo:doi	10.1038/s41598-018-34859-w
bibo:pmid	30413791
has license	cc-by
sha1sum (hex)	1185137c3c9ddbc0c91aa718179dadd11039f771
schema:url	https://doi.org/10.1038/s41598-018-34859-w
resource representing a document's title	Functional analysis of potential cleavage sites in the MERS-coronavirus spike protein
has PubMed Central identifier	PMC6226446
has PubMed identifier	30413791
schema:publication	Sci Rep
resource representing a document's body	covid:1185137c3c9ddbc0c91aa718179dadd11039f771#body_text
is schema:about of	named entity 'SPIKE PROTEIN' named entity 'SITES' named entity 'motif' named entity 'potential' named entity 'viral' named entity 'site' named entity 'robust' named entity 'essential' named entity 'cleavage' named entity 'coronavirus' named entity 'Functional analysis' named entity 'RIGID' named entity 'PRE' named entity 'ONE OF' covid:arg/1185137c3c9ddbc0c91aa718179dadd11039f771 named entity 'SITE' named entity 'ENTRY' named entity 'COMPATIBLE WITH' named entity 'VECTORS' named entity 'INDIRECT' named entity 'MOST LIKELY' named entity 'ACTIVATE' named entity 'EFFICIENT' named entity 'MUTATION' named entity 'INFECTIVITY' named entity 'MUTAGENIC' named entity 'TARGETS' named entity 'SEVERE DISEASE' named entity 'REQUIREMENT' named entity 'POTENTIAL' named entity 'PROTEASE' named entity 'USED' named entity 'SPIKE PROTEIN' named entity 'CLEAVAGE' named entity 'MERS' named entity 'POTENTIAL' named entity 'CORONAVIRUS' named entity 'FOUND' named entity 'SINGLE' named entity 'RELATIVE' named entity 'OUR' named entity 'TESTED' named entity 'ACTIVATION' named entity 'PROTEIN ACTIVATION' named entity 'BUT' named entity 'PROTEIN ' named entity 'ANTIVIRAL' named entity 'ANALYSIS' named entity 'CELLS' named entity 'ALL CELL' named entity 'RESULTS' named entity 'TMPRSS2' named entity 'ENDOGENOUS' named entity 'DEVELOPMENT' named entity 'IN KEEPING WITH' named entity 'TASK' named entity 'BEARING' named entity 'DOUBLE' named entity 'DISTINCT' named entity 'DID' named entity 'HOST CELL' named entity 'CATHEPSIN L' named entity 'ROBUST' named entity 'SEQUENCE' named entity 'S PROTEIN' named entity 'DEPENDENT' named entity 'EVIDENCE' named entity '80%' named entity 'REQUIRED' named entity 'OBTAINED' named entity 'AUXILIARY' named entity 'PANDEMIC' named entity 'FURIN' named entity 'RESPONSIBLE' named entity 'REPORTED' named entity 'SUBSEQUENT' named entity 'CLEAVAGE' named entity 'ARGININE'

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