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We know that SARS-CoV-2 appears to mainly attack animal cells by the ACE2 receptor, MERS-CoV by the DPP-4 receptor, and SARS-CoV also by the ACE2 receptor.

Do we know what receptors are targeted by the seasonal coronaviruses that primarily present as winter colds?

https://www.the-scientist.com/news-opinion/experimental-mers-treatments-target-host-cell-receptor-31759

https://jvi.asm.org/content/94/7/e00127-20.abstract

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The story for these "common cold" coronaviruses is a slightly complicated. Mostly, these target different receptors (than the SARS family), except for NL63.

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The host receptor is a major determinant of pathogenicity, tissue tropism and host range of the virus. The S protein comprises of two domains: S1 and S2. The interaction between the S1 domain and its cognate receptor triggers a conformational change in the S protein, which then promotes membrane fusion between the viral and cell membrane through the S2 domain. Today, the main host cell receptors utilised by all HCoVs are known: aminopeptidase N by HCoV-229E, angiotensin-converting enzyme 2 (ACE2) by SARS-CoV and HCoV-NL63, dipeptidyl peptidase 4 (DPP4) by MERS-CoV and 9-O-acetylated sialic acid by HCoV-OC43 and HCoV-HKU1.

Apart from the conventional endosomal route of entry, some CoVs may also gain entry into the cell via the non-endosomal pathway, or a combination of both. The low pH in the cellular environment and endosomal cysteine protease cathepsins may help to facilitate membrane fusion and endosomal CoV cell entry . Recent evidence has supported the role of cathepsin L in SARS-CoV and MERS-CoV entry. Other host proteases, such as transmembrane protease serine 2 (TMPRSS2) and airway trypsin-like protease TMPRSS11D, could also perform S1/S2 cleavage to activate the S protein for non-endosomal virus entry at the cell plasma membrane during HCoV-229E and SARS-CoV infection. In addition, MERS-CoV is also activated by furin, a serine endopeptidase that has been implicated in the cell entry of other RNA viruses and S1/S2 cleavage during viral egress.

It's worth reading some of the more in-depth papers on how NL63 entry differs from SARS (despite both using ACE2):

Here we show that SARS-CoV, but not HCoV-NL63, utilizes the enzymatic activity of the cysteine protease cathepsin L to infect ACE2-expressing cells. Inhibitors of cathepsin L blocked infection by SARS-CoV and by a retrovirus pseudotyped with the SARS-CoV spike (S) protein but not infection by HCoV-NL63 or a retrovirus pseudotyped with the HCoV-NL63 S protein. Expression of exogenous cathepsin L substantially enhanced infection mediated by the SARS-CoV S protein and by filovirus GP proteins but not by the HCoV-NL63 S protein or the vesicular stomatitis virus G protein. Finally, an inhibitor of endosomal acidification had substantially less effect on infection mediated by the HCoV-NL63 S protein than on that mediated by the SARS-CoV S protein. Our data indicate that two coronaviruses that utilize a common receptor nonetheless enter cells through distinct mechanisms.

https://jvi.asm.org/content/82/17/8887:

The S protein in the SARS-CoV spike apparently exposes a protease-accessible loop between the S1 and S2 subunits that can be targeted by different enzymes, such as cathepsin L, trypsin, and, under physiological conditions, local enzymes such as elastase. Consistent with the presence of such a loop, the syncytium-inducing capacity of expressed SARS-CoV S protein was dramatically enhanced after the introduction of a functional furin cleavage site in the S1/S2 junction region (8, 14). No such loop has been detected yet in spikes of HCoV-NL63 or of most other subgroup 1 coronaviruses. The resistance of the HCoV-NL63 spike ectodomain to cleavage by cathepsin L and trypsin that we observed here is in agreement with our inability to inhibit infection with HCoV-NL63 or an NL63 spike protein-pseudotyped retrovirus by using a broad spectrum of protease inhibitors (10). It is conceivable that during its low-pH-independent cell entry, HCoV-NL63 uses an alternative, possibly nonproteolytic way to activate the fusion function.

So yeah, it looks easier to block SARS than even the NL63 common cold using the same receptor...

A more recent paper, taking into account SARS-CoV-2 (Covid-19) has proposed that the more general distinction between the common colds and the more deadly coronaviruses is that:

S glycoprotein trimers found in highly pathogenic human coronaviruses appear to exist in partially opened states, while they remain largely closed in human coronaviruses associated with common colds. [...] most pathogenic coronaviruses will exhibit S glycoprotein trimers spontaneously sampling closed and open conformations, as is the case for SARS-CoV-2, SARS-CoV and MERS-CoV.

Also of note is that 229E and NL63 despite using different receptors are fairly related to each other, prompting the title of one paper "close yet still so far [apart]". (Those two viruses have 65% sequence identity, in retrospect less than SARS and SARS-CoV-2 similarity of around 80%.) But also

ACE2 belongs to the same protease family as CD13 [(also known as aminopeptidase N)]

Also of some interest, in some immunoassay SARS scored as a mix of 229E and NL63 response (plus some specific response). And an article on the putative common origin of 229E and NL63 in African bats.

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