The
spike protein tilts towards the host cell membrane so that it can bind to its
primary sugar receptor. This interaction then triggers opening of the spike so
that it can bind to a protein receptor that is required for cell entry. Credit:
Utrecht University, created with BioRender.com
Researchers
from the Utrecht University have uncovered a sophisticated mechanism by which
coronavirus spike proteins can be activated for cell entry. The study,
published in the journal Nature,
used powerful microscopes and computer simulations to reveal how a tiny sugar
molecule binds to a human coronavirus spike and triggers exposure of components
that are required to invade the host cell.
These findings provide new fundamental
insights into the complex mechanisms that coronavirus may use to evade the
immune system and initiate an infection.
Coronavirus spikes play a crucial role
in virus attachment and entry into our cells. An in-depth understanding of
these proteins is important because they are key factors for transmission
between species and the main targets for neutralizing antibodies.
To breach the host cell and deliver the viral genome, spike proteins must switch from a closed to an open state. This exposes a receptor binding domain, which then latches onto a protein receptor required for entry. For the most notorious coronaviruses, i.e. those causing SARS, MERS and COVID-19, the spikes can freely alternate between these two states. However, the spike proteins from other human and animal coronaviruses have only been visualized in the closed state.
A sugar-based receptor binds to the human
coronavirus HKU1 spike protein and triggers opening. This ‘activates’ the spike
for the next steps in cell entry. Credit: Utrecht University
This has led to the idea that most
coronavirus spike proteins might not just randomly switch between states, but
that there could be specific biological cues that trigger them to open.
"Coronavirus attachment may be even more sophisticated than appreciated so
far," said study author Daniel Hurdiss.
To investigate this long-standing
puzzle, senior authors Raoul de Groot and Daniel Hurdiss (Section of Virology,
Faculty of Veterinary Medicine, Utrecht University) focused on the spike
protein of human coronavirus HKU1, which, like most spikes, has only been
visualized in the closed state. Collectively, the four common cold
coronaviruses (HKU1, OC43, NL63 and 229E) are estimated to cause 15 to 30%
of respiratory tract infections each year.
Previous research from the lab
demonstrated that the HKU1 spike protein critically depends on binding to a
specific sugar molecule, but the reason for this remained unknown. In the
present study the authors discovered that sugar binding induces opening of the
spike protein and exposure of the receptor binding domain, required for
subsequent entry steps. The Utrecht researchers therefore found a biomolecular
mechanism that was hitherto unknown to science. "It's a fine-tuned sugar
switch," says Hurdiss.
"From the viruses'
perspective, it's a clever way of keeping your Achilles heel, the receptor
binding domain, hidden until the most opportune moment. Our findings paint a
more elaborate picture of coronavirus attachment, with possibilities of dual receptor
usage as a means of immune escape."
A sugar-based receptor binds to the human
coronavirus HKU1 spike protein and triggers opening. This ‘activates’ the spike
for the next steps in cell entry. Credit: Utrecht University
Cascade of conformational changes
Like piecing together a movie reel
from individual frames, Matti Pronker (Faculty of Science, Utrecht University
and first author of the study) modeled each conformation of the spike and
deduced a stepwise series of events induced by sugar binding. Working together
with Robert Creutznacher (Faculty of Veterinary Medicine, Utrecht University),
and Martin Frank, computational chemist from Biognos AB, they were able to
provide an explanation for how a tiny sugar molecule causes a cascade of
conformational changes in this comparatively giant macromolecular complex.
"It's like a butterfly effect," says Pronker. "It was intriguing to see
how small and local conformational changes, induced by the sugar binding,
trigger larger domain movements and eventually spike opening. Years of research
into coronavirus-sugar interactions have culminated in this work," says De
Groot.
The
sugar molecule (pink) binds to the sugar-binding site (gray and yellow),
located in the HKU1 spike protein, and stabilizes a conformational that
ultimately results in spike opening. Credit: Utrecht University
"This
has very much been a joint multidisciplinary effort, profiting from the unique
expertise of Geert-Jan Boons and Martin Frank, and with Yifei Lang, Zeshi Li
and Ruben Hulswit laying the foundation of the present study."
"Our findings suggest the possibility of coronaviruses relying on multi-receptor usage with binding to sugar- or protein-based priming receptors serving as a biological cue to activate the spikes for subsequent attachment and entry steps. At the virology group, we will continue to investigate how coronaviruses bind to and enter their host cells. Such studies are of importance for understanding virus-host interactions and zoonotic transmission as well as for the development of effective countermeasures."
Source: Revealing the 'secrets' of coronavirus cell entry (phys.org)
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