Spike (S) glycoprotein (sometimes also called spike protein,
formerly known as E2
) is the largest of the four major
structural proteins found in
coronaviruses.
The spike protein assembles into
trimers that form large structures, called spikes or
peplomers,
that project from the surface of the
virion.
The distinctive appearance of these spikes when visualized using
negative stain transmission electron microscopy
Transmission electron microscopy (TEM) is a microscopy technique in which a beam of electrons is transmitted through a specimen to form an image. The specimen is most often an ultrathin section less than 100 nm thick or a suspension on a ...
, "recalling the
solar corona",
gives the virus family its name.
The function of the spike
glycoprotein is to mediate
viral entry into the
host cell by first interacting with molecules on the exterior cell surface and then fusing the viral and cellular
membranes
A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. Bi ...
. Spike glycoprotein is a
class I fusion protein
Membrane fusion proteins (not to be confused with chimeric or fusion proteins) are proteins that cause fusion of biological membranes. Membrane fusion is critical for many biological processes, especially in eukaryotic development and viral entry. ...
that contains two regions, known as S1 and S2, responsible for these two functions. The S1 region contains the receptor-binding
domain
Domain may refer to:
Mathematics
*Domain of a function, the set of input values for which the (total) function is defined
** Domain of definition of a partial function
** Natural domain of a partial function
**Domain of holomorphy of a function
* ...
that binds to receptors on the cell surface. Coronaviruses use a very diverse range of receptors;
SARS-CoV (which causes
SARS) and
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
(which causes
COVID-19
Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease quick ...
) both interact with
angiotensin-converting enzyme 2 (ACE2). The S2 region contains the
fusion peptide and other fusion infrastructure necessary for membrane fusion with the host cell, a required step for infection and
viral replication. Spike glycoprotein determines the virus'
host range (which organisms it can infect) and
cell tropism (which cells or tissues it can infect within an organism).
Spike glycoprotein is highly
immunogenic.
Antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of ...
against spike glycoprotein are found in patients recovered from SARS and COVID-19.
Neutralizing antibodies target
epitopes on the receptor-binding domain.
Most
COVID-19 vaccine development efforts in response to the
COVID-19 pandemic
The COVID-19 pandemic, also known as the coronavirus pandemic, is an ongoing global pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel virus was first identi ...
aim to activate the
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
against the spike protein.
Spike glycoprotein is not the main determinant of
pathogenicity, which are other proteins that remain to be identified, but its
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
s do confer the virus the ability to
evade immunity.
Structure
The spike protein is very large, often 1200-1400
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
residues long;
it is 1273 residues in
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
.
It is a
single-pass transmembrane protein
A single-pass membrane protein also known as single-spanning protein or bitopic protein is a transmembrane protein that spans the lipid bilayer only once. These proteins may constitute up to 50% of all transmembrane proteins, depending on the orga ...
with a short
C-terminal tail on the interior of the virus, a
transmembrane helix, and a large
N-terminal ectodomain exposed on the virus exterior.
Spike glycoprotein forms
homotrimers in which three copies of the protein interact through their ectodomains.
The trimer structures have been described as club- pear-, or petal-shaped.
Each spike protein contains two regions known as S1 and S2, and in the assembled trimer the S1 regions at the N-terminal end form the portion of the protein furthest from the viral surface while the S2 regions form a flexible "stalk" containing most of the
protein-protein interactions that hold the trimer in place.
S1
The S1 region of the spike glycoprotein is responsible for interacting with receptor molecules on the surface of the host cell in the first step of
viral entry.
S1 contains two
domains, called the N-terminal domain (NTD) and C-terminal domain (CTD),
sometimes also known as the A and B domains.
Depending on the coronavirus, either or both domains may be used as receptor-binding domains (RBD). Target receptors can be very diverse, including
cell surface receptor proteins and sugars such as
sialic acids as receptors or coreceptors.
In general, the NTD binds sugar molecules while the CTD binds proteins, with the exception of
mouse hepatitis virus which uses its NTD to interact with a protein receptor called
CEACAM1.
The NTD has a
galectin
Galectins are a class of proteins that bind specifically to β-galactoside sugars, such as ''N''-acetyllactosamine (Galβ1-3GlcNAc or Galβ1-4GlcNAc), which can be bound to proteins by either N-linked or O-linked glycosylation. They are also te ...
-like
protein fold, but binds sugar molecules somewhat differently than galectins.
The CTD is responsible for the interactions of
MERS-CoV with its receptor
dipeptidyl peptidase-4,
and those of
SARS-CoV and
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
with their receptor
angiotensin-converting enzyme 2 (ACE2). The CTD of these viruses can be further divided into two subdomains, known as the core and the extended loop or receptor-binding motif (RBM), where most of the residues that directly contact the target receptor are located.
There are subtle differences, mainly in the RBM, between the SARS-CoV and SARS-CoV-2 spike proteins' interactions with ACE2.
Comparisons of spike proteins from multiple coronaviruses suggest that divergence in the RBM region can account for differences in target receptors, even when the core of the S1 CTD is structurally very similar.
Within coronavirus lineages, as well as across the four major coronavirus subgroups, the S1 region is less well
conserved than S2, as befits its role in interacting with virus-specific host cell receptors.
Within the S1 region, the NTD is more highly conserved than the CTD.
S2
The S2 region of spike glycoprotein is responsible for
membrane fusion between the
viral envelope and the
host cell, enabling entry of the virus'
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ...
into the cell.
The S2 region contains the
fusion peptide, a stretch of mostly
hydrophobic
In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, ...
amino acids whose function is to enter and destabilize the host cell membrane.
S2 also contains two
heptad repeat
The heptad repeat is an example of a structural motif that consists of a repeating pattern of seven amino acids:
''a b c d e f g''
H P P H C P C
where H represents hydrophobic residues, C represents, typically, charged residues, and P repres ...
subdomains known as HR1 and HR2, sometimes called the "fusion core" region.
These subdomains undergo dramatic
conformational changes during the fusion process to form a
six-helix bundle, a characteristic feature of the
class I fusion proteins.
The S2 region is also considered to include the
transmembrane helix and
C-terminal tail located in the interior of the virion.
Relative to S1, the S2 region is very well
conserved among coronaviruses.
Post-translational modifications
Spike glycoprotein is heavily
glycosylated
Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
through
N-linked glycosylation.
Studies of the
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
spike protein have also reported
O-linked glycosylation in the S1 region.
The C-terminal tail, located in the interior of the virion, is enriched in
cysteine residues and is
palmitoylated
Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine (''S''-palmitoylation) and less frequently to serine and threonine (''O''-palmitoylation) residues of proteins, which are typically membrane prot ...
.
Spike proteins are activated through
proteolytic cleavage. They are cleaved by host cell
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
s at the S1-S2 boundary and later at what is known as the S2' site at the N-terminus of the fusion peptide.
Conformational change
Like other
class I fusion proteins, the spike protein undergoes a very large
conformational change during the fusion process.
Both the pre-fusion and post-fusion states of several coronaviruses, especially
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
, have been studied by
cryo-electron microscopy
Cryogenic electron microscopy (cryo-EM) is a cryomicroscopy technique applied on samples cooled to cryogenic temperatures. For biological specimens, the structure is preserved by embedding in an environment of vitreous ice. An aqueous sample so ...
.
Functionally important
protein dynamics Proteins are generally thought to adopt unique structures determined by their amino acid sequences. However, proteins are not strictly static objects, but rather populate ensembles of (sometimes similar) conformations. Transitions between these stat ...
have also been observed within the pre-fusion state, in which the relative orientations of some of the S1 regions relative to S2 in a trimer can vary. In the closed state, all three S1 regions are packed closely and the region that makes contact with host cell receptors is
sterically
Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...
inaccessible, while the open states have one or two S1 RBDs more accessible for receptor binding, in an open or "up" conformation.
Expression and localization
The
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
encoding the spike protein is located toward the
3' end of the virus's
positive-sense RNA
In molecular biology and genetics, the sense of a nucleic acid molecule, particularly of a strand of DNA or RNA, refers to the nature of the roles of the strand and its complement in specifying a sequence of amino acids. Depending on the context, ...
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ...
, along with the genes for the other three structural proteins and various virus-specific
accessory protein A viral regulatory and accessory protein is a type of viral protein that can play an indirect role in the function of a virus.
An example is Nef.
References
Further reading
*
Viral proteins
{{virus-stub ...
s.
Protein trafficking
:''This article deals with protein targeting in eukaryotes unless specified otherwise.''
Protein targeting or protein sorting is the biological mechanism by which proteins are transported to their appropriate destinations within or outside the c ...
of spike proteins appears to depend on the coronavirus subgroup: when
expressed in isolation without other viral proteins, spike proteins from
betacoronaviruses are able to reach the
cell surface, while those from
alphacoronaviruses and
gammacoronaviruses are retained intracellularly. In the presence of the
M protein, spike protein trafficking is altered and instead is retained at the
ERGIC
The vesicular-tubular cluster (VTC), also referred to as the endoplasmic-reticulum–Golgi intermediate compartment (ERGIC), is an organelle in eukaryotic cells. This compartment mediates trafficking between the endoplasmic reticulum (ER) and Golgi ...
, the site at which viral assembly occurs.
In
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
, both the M and the
E protein modulate spike protein trafficking through different mechanisms.
The spike protein is not required for viral assembly or the formation of
virus-like particles;
however, presence of spike may influence the size of the envelope.
Incorporation of the spike protein into virions during assembly and budding is dependent on
protein-protein interactions with the M protein through the C-terminal tail.
Examination of virions using
cryo-electron microscopy
Cryogenic electron microscopy (cryo-EM) is a cryomicroscopy technique applied on samples cooled to cryogenic temperatures. For biological specimens, the structure is preserved by embedding in an environment of vitreous ice. An aqueous sample so ...
suggests that there are approximately 25
to 100 spike trimers per virion.
Function
The spike protein is responsible for
viral entry into the
host cell, a required early step in
viral replication. It is
essential for replication.
It performs this function in two steps, first binding to a receptor on the surface of the host cell through interactions with the S1 region, and then fusing the viral and cellular membranes through the action of the S2 region.
The location of fusion varies depending on the specific coronavirus, with some able to enter at the
plasma membrane and others entering from
endosomes after
endocytosis.
Attachment
The interaction of the receptor-binding domain in the S1 region with its target receptor on the cell surface initiates the process of viral entry. Different coronaviruses target different cell-surface receptors, sometimes using sugar molecules such as
sialic acids, or forming
protein-protein interactions with proteins exposed on the cell surface.
Different coronaviruses vary widely in their target receptor. The presence of a target receptor that S1 can bind is a determinant of
host range and
cell tropism.
Proteolytic cleavage
Proteolytic cleavage of the spike protein, sometimes known as "priming", is required for membrane fusion. Relative to other class I fusion proteins, this process is complex and requires two cleavages at different sites, one at the S1/S2 boundary and one at the S2' site to release the
fusion peptide.
Coronaviruses vary in which part of the viral life cycle these cleavages occur, particularly the S1/S2 cleavage. Many coronaviruses are cleaved at S1/S2 before viral exit from the virus-producing cell, by
furin and other
proprotein convertase Proprotein convertases (PPCs) are a family of proteins that activate other proteins. Many proteins are inactive when they are first synthesized, because they contain chains of amino acids that block their activity. Proprotein convertases remove thos ...
s;
in
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
a polybasic furin cleavage site is present at this position.
Others may be cleaved by extracellular proteases such as
elastase, by proteases located on the cell surface after receptor binding, or by proteases found in
lysosome
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane p ...
s after
endocytosis.
The specific proteases responsible for this cleavage depends on the virus, cell type, and local environment.
In
SARS-CoV, the
serine protease TMPRSS2 is important for this process, with additional contributions from
cysteine protease
Cysteine proteases, also known as thiol proteases, are hydrolase enzymes that degrade proteins. These proteases share a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad or dyad.
Discovered by Gopal ...
s
cathepsin B and
cathepsin L in endosomes.
Trypsin and trypsin-like proteases have also been reported to contribute.
In
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
, TMPRSS2 is the primary protease for S2' cleavage, and its presence is reported to be essential for viral infection,
with cathepsin L protease being functional, but not essential.
Membrane fusion
Like other
class I fusion proteins, the spike protein in its pre-fusion conformation is in a
metastable state.
A dramatic
conformational change is triggered to induce the
heptad repeat
The heptad repeat is an example of a structural motif that consists of a repeating pattern of seven amino acids:
''a b c d e f g''
H P P H C P C
where H represents hydrophobic residues, C represents, typically, charged residues, and P repres ...
s in the S2 region to refold into an extended
six-helix bundle, causing the
fusion peptide to interact with the cell membrane and bringing the viral and cell membranes into close proximity.
Receptor binding and proteolytic cleavage (sometimes known as "priming") are required, but additional triggers for this conformational change vary depending on the coronavirus and local environment.
''
In vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...
'' studies of
SARS-CoV suggest a dependence on
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar ...
concentration.
Unusually for coronaviruses,
infectious bronchitis virus, which infects birds, can be triggered by low
pH alone; for other coronaviruses, low pH is not itself a trigger but may be required for activity of proteases, which in turn are required for fusion.
The location of membrane fusion—at the
plasma membrane or in
endosomes—may vary based on the availability of these triggers for conformational change.
Fusion of the viral and cell membranes permits the entry of the virus'
positive-sense RNA
In molecular biology and genetics, the sense of a nucleic acid molecule, particularly of a strand of DNA or RNA, refers to the nature of the roles of the strand and its complement in specifying a sequence of amino acids. Depending on the context, ...
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ...
into the host cell
cytosol, after which
expression of viral proteins begins.
In addition to fusion of viral and host cell membranes, some coronavirus spike proteins can initiate membrane fusion between infected cells and neighboring cells, forming
syncytia.
This behavior can be observed in infected cells in
cell culture.
Syncytia have been observed in patient tissue samples from infections with
SARS-CoV,
MERS-CoV, and
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
,
though some reports highlight a difference in syncytia formation between the SARS-CoV and SARS-CoV-2 spikes attributed to sequence differences near the S1/S2 cleavage site.
Immunogenicity
Because it is exposed on the surface of the virus, the spike protein is a major
antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respon ...
to which
neutralizing antibodies are developed.
Its extensive
glycosylation can serve as a
glycan shield that hides
epitopes from the
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
.
Due to the outbreak of
SARS and the
COVID-19 pandemic
The COVID-19 pandemic, also known as the coronavirus pandemic, is an ongoing global pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel virus was first identi ...
, antibodies to
SARS-CoV and
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
spike proteins have been extensively studied. Antibodies to the SARS-CoV and SARS-CoV-2 spike proteins have been identified that target epitopes on the receptor-binding domain
or interfere with the process of conformational change.
The majority of antibodies from infected individuals target the receptor-binding domain.
COVID-19 response
Vaccines
In response to the
COVID-19 pandemic
The COVID-19 pandemic, also known as the coronavirus pandemic, is an ongoing global pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel virus was first identi ...
, a number of
COVID-19 vaccines have been developed using a variety of technologies, including
mRNA vaccines and
viral vector vaccines. Most vaccine development has targeted the spike protein.
Building on techniques previously used in vaccine research aimed at
respiratory syncytial virus and
SARS-CoV, many SARS-CoV-2 vaccine development efforts have used constructs that include
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
s to stabilize the spike protein's pre-fusion conformation, facilitating development of antibodies against
epitopes exposed in this conformation.
Monoclonal antibodies
Monoclonal antibodies that target the spike protein have been developed as
COVID-19 treatments. As of July 8, 2021, three monoclonal antibody products had received
Emergency Use Authorization in the United States:
bamlanivimab/etesevimab
Bamlanivimab/etesevimab is a combination of two monoclonal antibodies, bamlanivimab and etesevimab, administered together via intravenous infusion as a treatment for COVID-19. Both types of antibody target the surface spike protein of SARS� ...
,
casirivimab/imdevimab
Casirivimab/imdevimab, sold under the brand name REGEN‑COV among others, Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. is a combination medicine ...
,
and
sotrovimab.
Bamlanivimab/etesevimab was not recommended in the United States due to the increase in
SARS-CoV-2 variant
There are many variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19). Some are believed, or have been stated, to be of particular importance due to their potential ...
s that are less susceptible to these antibodies.
SARS-CoV-2 variants
Throughout the
COVID-19 pandemic
The COVID-19 pandemic, also known as the coronavirus pandemic, is an ongoing global pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel virus was first identi ...
, the
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ...
of SARS-CoV-2 viruses was
sequenced many times, resulting in identification of thousands of distinct
variants.
Many of these possess
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
s that change the
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
sequence
In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is called ...
of the spike protein. In a
World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level o ...
analysis from July 2020, the spike (''S'') gene was the second most frequently mutated in the genome, after ''
ORF1ab'' (which encodes most of the virus'
nonstructural proteins).
The
evolution rate in the spike gene is higher than that observed in the genome overall.
Analyses of SARS-CoV-2 genomes suggests that some sites in the spike protein sequence, particularly in the receptor-binding domain, are of evolutionary importance
and are undergoing
positive selection.
Spike protein mutations raise concern because they may affect
infectivity or
transmissibility, or facilitate
immune escape.
The mutation
D614
G has arisen independently in multiple viral lineages and become dominant among sequenced genomes;
it may have advantages in infectivity and transmissibility
possibly due to increasing the density of spikes on the viral surface,
increasing the proportion of binding-competent conformations or improving stability,
but it does not affect vaccines.
The mutation N501Y is common to the Alpha, Beta, Gamma and Omicron
Variants of SARS-CoV-2
There are many variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19). Some are believed, or have been stated, to be of particular importance due to their potent ...
and has contributed to enhanced infection and transmission,
reduced vaccine efficacy,
and the ability of SARS-CoV-2 to infect new rodent species.
The mutation P681R alters the furin cleavage site, and has been responsible for increased infectivity, transmission and global impact of the
SARS-CoV-2 Delta variant
The Delta variant (B.1.617.2) was a variant of SARS-CoV-2, the virus that causes COVID-19. It was first detected in India in late 2020. The Delta variant was named on 31 May 2021 and had spread to over 179 countries by 22 November 2021. The ...
.
Mutations at position
E484, particularly
E484
K, have been associated with
immune escape and reduced
antibody
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of t ...
binding.
The
SARS-CoV-2 Omicron variant
Omicron (B.1.1.529) is a variant of SARS-CoV-2 first reported to the World Health Organization (WHO) by the Network for Genomics Surveillance in South Africa on 24 November 2021. It was first detected in Botswana and has spread to become the ...
is notable for having an unusually high number of mutations in the spike protein.
The SARS CoV-2 spike gene (S gene, S-gene) mutation 69–70del (Δ69-70) causes a
TaqPath PCR test probe to not bind to its S gene target, leading to S gene target failure (SGTF) in SARS CoV-2 positive samples. This effect was used as a marker to monitor the propagation of the
Alpha variant and the
Omicron variant.
Additional Key Role in Illness
In 2021, Circulation Research and Salk had a new study that proves COVID-19 can be also a vascular disease, not only respiratory disease. The scientists created an “pseudovirus”, surrounded by SARS-CoV-2 spike proteins but without any actual virus. And pseudovirus resulted in damaging lungs and arteries of animal models. It shows SARS-CoV-2 spike protein alone can cause vascular disease and could explain some covid-19 patients who suffered from strokes, or other vascular problems in other parts of human body at the same time. The team replicated the process by removing replicating capabilities of virus and showed the same damaging effect on vascular cells again.
Misinformation
During the
COVID-19 pandemic
The COVID-19 pandemic, also known as the coronavirus pandemic, is an ongoing global pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The novel virus was first identi ...
,
anti-vaccination misinformation about COVID-19
False information, including intentional disinformation and conspiracy theories, about the scale of the COVID-19 pandemic and the Investigations into the origin of COVID-19, origin, prevention, diagnosis, and treatment of the disease has been ...
circulated on social media platforms related to the spike protein's role in
COVID-19 vaccines. Spike proteins were said to be dangerously "
cytotoxic" and mRNA vaccines containing them therefore in themselves dangerous. Spike proteins are not cytotoxic or dangerous. Spike proteins were also said to be "shed" by vaccinated people, in an erroneous allusion to the phenomenon of
vaccine-induced viral shedding, which is a rare effect of
live-virus vaccines unlike those used for COVID-19. "Shedding" of spike proteins is not possible.
Evolution, conservation and recombination
The
class I fusion protein
Membrane fusion proteins (not to be confused with chimeric or fusion proteins) are proteins that cause fusion of biological membranes. Membrane fusion is critical for many biological processes, especially in eukaryotic development and viral entry. ...
s, a group whose well-characterized examples include the coronavirus spike protein,
influenza virus hemagglutinin, and
HIV Gp41, are thought to be evolutionarily related.
The S2 region of the spike protein responsible for membrane fusion is more highly
conserved than the S1 region responsible for receptor interactions.
The S1 region appears to have undergone significant
diversifying selection
Disruptive selection, also called diversifying selection, describes changes in population genetics in which extreme values for a trait are favored over intermediate values. In this case, the variance of the trait increases and the populatio ...
.
Within the S1 region, the N-terminal domain (NTD) is more conserved than the C-terminal domain (CTD).
The NTD's
galectin
Galectins are a class of proteins that bind specifically to β-galactoside sugars, such as ''N''-acetyllactosamine (Galβ1-3GlcNAc or Galβ1-4GlcNAc), which can be bound to proteins by either N-linked or O-linked glycosylation. They are also te ...
-like
protein fold suggests a relationship with structurally similar cellular proteins from which it may have evolved through gene capture from the host.
It has been suggested that the CTD may have evolved from the NTD by
gene duplication.
The surface-exposed position of the CTD, vulnerable to the host
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
, may place this region under high
selective pressure
Any cause that reduces or increases reproductive success in a portion of a population potentially exerts evolutionary pressure, selective pressure or selection pressure, driving natural selection. It is a quantitative description of the amount of ...
.
Comparisons of the structures of different coronavirus CTDs suggests they may be under diversifying selection
and in some cases, distantly related coronaviruses that use the same cell-surface receptor may do so through
convergent evolution
Convergent evolution is the independent evolution of similar features in species of different periods or epochs in time. Convergent evolution creates analogous structures that have similar form or function but were not present in the last com ...
.
References
External links
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{{Viral proteins
Coronavirus proteins
Viral protein class
Viral structural proteins