Structure of Coronavirus:
Life cycle
of SARS CoV-2
Attachment
and entry
The virus attached with the host cell by the spike protein and
its receptor. The receptor binding domain (RBD) on spike protein recognizes
the angiotensin-converting enzyme-2 (ACE2) receptor on host cell and attaches
to it. After attachment with host cell, virus is able to enter the host
cell. There are two different ways to enter the host cell. The mechanism of
entrance into host cell is depends on the host protease, protease
cleave and activate the receptor-attached spike protein.
The first mechanism SARS CoV-2 follow to enter the host cell is endocytosis and uptake of
the virus in an endosome. The receptor-attached spike protein is then cleaved
and activated by the host's pH-dependent cysteine protease cathepsin
L. When this receptor-attached spike protein gets activated introduces
a conformational change, and the later fusion of the viral envelope with
the endosomal wall occurs.
In other mechanism, the SARS CoV-2 can enter the host cell directly by proteolytic cleavage
of the receptor-attached spike protein by the
host's TMPRSS2 or TMPRSS11D serine proteases at the
cell surface. In the SARS coronavirus, the activation of the C-terminal
part of the spike protein triggers the fusion of the viral envelope with
the host cell membrane by inducing conformational changes.
Genome translation
After fusion the viral nucleocapsid passes into
the cytoplasm, where the viral genome is released. The viral genome acts
as a messenger RNA (mRNA), and the host cell's ribosome translates two-thirds
of the genome into two large overlapping polyproteins, pp1a and pp1ab.
These polyproteins have their very own proteases, PLpro
and 3CLpro, which cleave the polyproteins at specific sites. Polyprotein
pp1ab yields 16 nonstructural proteins (nsp1 to nsp16) after cleavage. Product
proteins include various replication proteins such as RNA-dependent RNA
polymerase (RdRp), RNA helicase, and exoribonuclease (ExoN).
Replication and transcription
Many nonstructural replication proteins collectively form
a multi-protein replicase-transcriptase complex (RTC). RNA-dependent
RNA polymerase (RdRp) is the main replicase-transcriptase protein. This protein
directly involved in the replication and transcription of
RNA from an RNA strand. The other nonstructural proteins of the complex assist
in the replication and transcription process.
(Image source: Smith EC, Denison MR
(2013). Coronaviruses as DNA Wannabes: A New Model for the Regulation of RNA
Virus Replication Fidelity. PLoS Pathog 9(12): e1003760.)
The protein nsp15 acts as a 3'-5' exoribonuclease and
provides a proofreading function to the complex which the
RNA-dependent RNA polymerase dos’nt has. Proteins nsp7 and nsp8 form a hexadecameric
sliding clamp as part of the complex which significantly increases
the processivity of the RNA-dependent RNA polymerase. Due to large
genome size the coronaviruses needs the increased fidelity and processivity
during RNA synthesis.
One of the main roles of the (RTC) is to transcribe the viral
genome. RdRp directly mediates the synthesis of negative-sense
subgenomic RNA molecules from the positive-sense genomic RNA. After transcription
of these negative-sense subgenomic RNA molecules, transcription of their
corresponding positive-sense mRNAs takes place.
The other important function of the RTC is to replicate the
viral genome. Replication of positive-sense genomic RNA is from the
negative-sense genomic RNA.
This replicated positive-sense genomic RNA becomes the genome of
the progeny viruses. The various smaller mRNAs are transcribes from the
last third of the virus genome. These mRNAs are translated into the four
structural proteins (S, E, M, and N) that will become part of the progeny virus
particles and also eight other accessory proteins which assist the virus.
Assembly and release
RNA translation takes place inside the endoplasmic
reticulum. The viral structural proteins S, E and M move along the secretory
pathway into the Golgi intermediate compartment. There, the M proteins
direct most protein-protein interactions required for assembly of viruses
following its binding to the nucleocapsid. Progeny viruses are released from
the host cell by exocytosis through secretory vesicles.
(Image source:
No comments:
Post a Comment