#FEMSmicroBlog: Receptors of coronaviruses


There is a broad landscape of coronavirus spike protein interactions, with a diverse array of host cell receptors. The new review “Molecular diversity of coronavirus host cell entry receptors” in FEMS Microbiology Reviews puts into perspective recent findings on the SARS-CoV-2 receptor. The review focuses on the multi-pronged strategies that coronaviruses employ to initiate infection and covers topics such as coronavirus pathogenesis and spreading, as well as the molecular mechanisms underpinning spill-over events and cross-species transmission. #FascinatingMicrobes 


Like spikes on a crown

Coronaviruses are enveloped, positive-stranded RNA viruses that infect a wide range of mammals and birds. Since the beginning of the 21st century, the world has witnessed the successive emergence of several highly pathogenic human coronaviruses of bat origin.

These include severe acute respiratory syndrome coronavirus (SARS-CoV), the cause of the SARS epidemic in 2002-2003, Middle East respiratory syndrome coronavirus (MERS-CoV), which initiated a widespread epidemic in 2012 that is still ongoing, and more recently SARS-CoV-2, which is responsible for the current COVID-19 pandemic.

The coronavirus spike protein is the main determinant of viral entry. It is composed of two subunits, the S1 subunit that contains receptor-binding domains responsible for attachment to host cells, and the S2 subunit that holds the machinery necessary for fusion between the viral envelope and cellular membranes.

Its organization, along with its propensity to recombine and accumulate mutations, have led to the notion that the spike protein functions and evolves in a modular manner. Importantly, the spike protein governs to a large extent host tropism and cross-species transmission.

Coronavirus spike proteins have unique properties. They possess distinct receptor binding domains (RBDs) in the S1 N-terminal and C-terminal domains (NTD and CTD, respectively), granting a broad ability to bind to different types of receptors. Structural studies have highlighted these features and advanced our understanding of the mechanisms by which spike proteins bind to receptors and mediate membrane fusion.

Co-operative roles of the spike protein NTD and CTD receptor binding modules in coronavirus ecology. Schematic of coronavirus NTD and CTD subdomains with their complementary characteristics and roles in coronavirus tropism and host range. (For more details, see the full text.)


Diversity of coronavirus receptors in animal host cells

Decades of studies have enabled the field to uncover a wide array of animal host cell receptors for coronaviruses, with four main protein receptors currently known.

These include carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) used by the prototypical murine hepatitis virus (MHV) lineage A Betacoronavirus genus member, along with the membrane ectopeptidases such as aminopeptidase N (APN), used by members of the Alphacoronavirus and Deltacoronavirus genera; angiotensin-converting enzyme 2 (ACE2) used by the lineage B betacoronaviruses SARS-CoV and SARS-CoV-2, as well as the Alphacoronavirus NL63; and dipeptidyl peptidase 4 (DPP4), used by the lineage C betacoronavirus MERS-CoV.

In addition, various other host proteins have been proposed as attachment factors, receptors or co-receptors of coronaviruses. Our review highlights the phylogenetic relationships between the various spike proteins and the corresponding receptors, and showcases how structure-function studies of coronavirus receptor usage have allowed the emergence of fundamental concepts in the mechanistic understanding of coronavirus pathogenicity, spreading, and inter-species transmission.

Our review highlights the phylogenetic relationships between the various spike proteins and the corresponding receptors of coronaviruses, and […] the mechanistic understanding of coronavirus pathogenicity, spreading, and inter-species transmission.

— The authors of “Molecular diversity of coronavirus host cell entry receptors” in FEMS Microbiology Reviews

Protein receptors are not the only type of ligands coronavirus spike proteins are capable of binding to. It has been demonstrated that many coronaviruses can also bind to carbohydrates such as sialic acids and heparan sulfate.

This latter binding ability is perhaps less appreciated than the spike protein-receptor-binding capacity. However, carbohydrate binding can have important implications, notably for viral spreading to various tissue types and organs within a host. The review also discusses how carbohydrate binding could be an important parameter for inter-species transmission events, particularly from bats.

The sophisticated strategies coronaviruses employ to attach to target host cells, mirrors their complex evolutionary histories and their uncanny ability for adaptation and spread to new hosts.

This review offers insights into the molecular mechanisms regulating pathogenesis, spread, and zoonotic transmission of this fascinating group of viruses. While many unresolved questions remain, the studies covered in the review also provide some perspectives that may aid in formulating guidelines for future coronavirus pandemic preparedness.

About the author of this blog

Gary R. Whittaker (@whittakerIDlab) is Professor of Virology Microbiology and Immunology at Cornell University (US). He received a bachelor’s degree in Biochemistry and his Ph.D. in Microbiology from Leeds University (UK) where he studied the molecular biology and biochemistry of equine herpesvirus. He obtained postdoctoral training at Yale University (US) in the laboratory of Dr. Ari Helenius, studying the cell biology of influenza virus replication. Dr Whittaker’s laboratory focuses on influenza viruses and coronaviruses (SARS-CoV, SARS-CoV-2, MERS-CoV, feline coronaviruses), in particular on the structure and function of viral envelope proteins, novel vaccines, and diagnostic test development.

About this blog section

The section #FascinatingMicrobes for the #FEMSmicroBlog explains the science behind a paper and highlights the significance and broader context of a recent finding. One of the main goals is to share the fascinating spectrum of microbes across all fields of microbiology.

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