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Nature Microbiology @natmicrobiol.nature.com · Aug 11

#NewResearch

Cryo-EM structures of the full-length Junin virus and Machupo virus spike glycoprotein complexes stabilized in the prefusion conformation - analyses reveal features that regulate glycoprotein pH-dependent membrane fusion activity.

#MicroSky 🦠

www.nature.com/articles/s41...

Molecular organization of the New World arenavirus spike glycoprotein complex - Nature Microbiology

Cryo-EM structures of the full-length Junin virus and Machupo virus spike glycoprotein complexes stabilized in the prefusion conformation. Analyses reveal features that regulate glycoprotein pH-depend...

www.nature.com

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Aug 9

Though the Candid#1 vaccine is effective against JUNV, other lethal New World arenaviruses still pose a large public health risk 🌎with no specific medical countermeasures. The structures may serve as a basis for further rational design and development of therapeutics and vaccines

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Aug 9

A K33A substitution in the stable signal peptide (SSP) allowed for stabilization of the pre-fusion GPC, with molecular dynamics suggesting K33A stabilizes GPC by better accommodating membrane lipids in the SSP33 pocket, supported by our cryo-EM density

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Aug 9

Further structural and functional analyses also reveal the effect of specific residues in transmembrane and membrane proximal region on pH-mediated fusion, elucidating the attenuation mechanism of the JUNV Candid#1 vaccine

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Aug 9

These cryo-EM structures reveal notable differences between JUNV and MACV in GP1 organization at the apex and C terminus. The MACV GPC apex has a more open appearance due to its GP1 subunits slightly rotating outwards and clockwise 🔃compared to JUNV GP1 subunits

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Aug 9

Our @natmicrobiol.nature.com paper provides the most complete insight into the molecular organization of the JUNV and MACV GPCs yet 😲revealing new features not seen in previous structures, such as the TM helices and cytosolic portions, including ZBD

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Aug 9

New World arenaviruses, like Junin virus (JUNV) and Machupo virus (MACV), cause hemorrhagic fever with fatality rates as high as 30% predominantly in South America. To date, the only medical countermeasure against these viruses is the Candid#1 vaccine effective only against JUNV

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Aug 9

Excited to share our new @natmicrobiol.nature.com paper revealing the most complete arenavirus glycoprotein complex (GPC) structures to date 🤩 www.nature.com/articles/s41...

Molecular organization of the New World arenavirus spike glycoprotein complex - Nature Microbiology

Cryo-EM structures of the full-length Junin virus and Machupo virus spike glycoprotein complexes stabilized in the prefusion conformation. Analyses reveal features that regulate glycoprotein pH-depend...

www.nature.com

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Reposted

Cell - a Cell Press journal @cp-cell.bsky.social · Apr 5

Now online! Molecular basis for shifted receptor recognition by an encephalitic arbovirus

Molecular basis for shifted receptor recognition by an encephalitic arbovirus

Cryo-EM structures and mutational analyses reveal western equine encephalitis virus E2-E1 glycoprotein polymorphisms that determine shifted receptor usage and allow for sequence-based prediction of strain compatibility with human receptors.

dlvr.it

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Apr 4

Also sharing the terrific news piece by Jake Miller at HMS News on our latest paper! @cp-cell.bsky.social
hms.harvard.edu/news/how-sma...

How A Small Number of Mutations Can Fuel Outbreaks of Western Equine Encephalitis Virus

Study shows how spike protein changes determine the risk of viral outbreaks

hms.harvard.edu

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Apr 4

WEEV re-emerged in South America in 2023-2024 in a large outbreak, highlighting the critical need for preparedness. Using the structures, we identified E2 polymorphisms that predict WEEV strain receptor dependency, which will support environmental surveillance.

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Apr 4

Interesting tidbit in the story: a WEEV-related alphavirus that circulates on the east coast (EEEV territory) called highlands J virus (HJV) also uses PCDH10 as a receptor. It diverged from WEEV not that long ago and retained most PCDH10 contact residues.

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Apr 4

Some WEEV strains and EEEV both bind VLDLR at the LA1 and LA2 domains, suggesting that VLDLR LA1-LA2 decoy receptor may have broad activity against them. This molecule protected mice against lethal challenge by a WEEV strain that binds VLDLR.

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Apr 4

Strains isolated during epidemics of the early 20th century bind VLDLR and ApoER2 as additional receptors. Our structure of a 1941 strain bound by VLDLR revealed a distinct binding mode than other alphaviruses that bind LDLR-related proteins, such as EEEV, SFV or VEEV.

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Apr 4

We found a substitution in the E2 glycoprotein, L149Q, that would disrupt hydrophobic contact with PCDH10, and confirmed this mutation alone abolishes human PCDH10 binding. L149Q is found in all strains isolated in California and Texas in 2005, suggesting a wide geographic range.

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Apr 4

Protocadherin 10 (PCDH10) is a major receptor for WEEV. Multiple strains isolated in 2005 lost the ability to bind human and horse PCDH10, yet still bind avian PCDH10. Cryo-EM structures show identical binding mode of sparrow and human PCDH10.

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Apr 4

WEEV is a mosquito-borne alphavirus that caused widespread outbreaks in horses and humans in the early 20th century, but outbreak frequency and scale dramatically decreased since then. We previously found this “submergence” of WEEV was accompanied by shifted receptor recognition.🦟🐎

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Apr 4

Our study on the molecular basis of shifts in receptor recognition by western equine encephalitis virus (WEEV) in the past century, led by Xiaoyi Fan and @wanyuviridae.bsky.social , is online! 👏🎉
www.cell.com/cell/fulltex...

Molecular basis for shifted receptor recognition by an encephalitic arbovirus

Cryo-EM structures and mutational analyses reveal western equine encephalitis virus E2-E1 glycoprotein polymorphisms that determine shifted receptor usage and allow for sequence-based prediction of st...

www.cell.com

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Jan 2

Thank you to everyone who contributed, including @wanyuviridae.bsky.social, @jessicaoros.bsky.social, @hhvarnum.bsky.social, and everyone else!

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Jan 2

WEEV is not gone, as a 2023-24 South American outbreak caused >2500 horse and >200 human cases. Therefore, this information is critical to estimate the potential threat of any new WEEV strain, supporting environmental surveillance and outbreak preparedness @hhmi.bsky.social

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Jan 2

We also determined structures of an ancestral WEEV strain bound to VLDLR, revealing a distinct binding mode compared to other alphaviruses that bind LDLR-related receptors such as EEEV, SFV, or VEEV, indicating independent evolution of WEEV to bind VLDLR/ApoER2!

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Jan 2

To explain why recent WEEV strains such as 2005 Imperial 181 lost human PCDH10 binding, we identified a single amino acid change in the E2 glycoprotein (Q149), which disrupts ❌key hydrophobic contacts present in ancestral strains containing a conserved L149.

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Jan 2

Our new study defines WEEV amino acid polymorphisms that explain shifts in receptor usage. By using cryo-EM, we showed that PCDH10 binds the clefts between adjacent WEEV E2–E1 glycoprotein heterodimers, mimicking the binding mode of PCDH10 antiparallel homodimers.

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Jan 2

In our recent paper @nature, we identified the protocadherin PCDH10 as a receptor for WEEV and found that WEEV appears to have shifted away from using human and horse PCDH10, correlating to the decline in outbreaks ⤵️ www.nature.com/articles/s41...

Shifts in receptors during submergence of an encephalitic arbovirus - Nature

Knockout studies using CRISPR–Cas9 identify PCDH10 as a selective host cellular receptor for western equine encephalitis virus.

www.nature.com

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abrahamlabhms.bsky.social @abrahamlabhms.bsky.social · Jan 2

Transmitted by mosquitoes 🦟 to humans and horses, western equine encephalitis virus (WEEV) has caused several outbreaks throughout the 20th century, but decreases in outbreak frequency and scale indicate a submergence of WEEV.

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