Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently emerged pathogenic human coronavirus that belongs to the sarbecovirus lineage of the genus Betacoronavirus. The ancestor strain has evolved into a number of variants of concern, with the Omicron variant of concern now having many distinct sublineages. The ongoing COVID-19 pandemic caused by SARS-CoV-2 has caused serious damage to public health and the global economy, and one strategy to combat COVID-19 has been the development of broadly neutralizing antibodies for prophylactic and therapeutic use. Many are in preclinical and clinical development, and a few have been approved for emergency use. Here we summarize neutralizing antibodies that target four key regions within the SARS-CoV-2 spike (S) protein, namely the N-terminal domain and the receptor-binding domain in the S1 subunit, and the stem helix region and the fusion peptide region in the S2 subunit. Understanding the characteristics of these broadly neutralizing antibodies will accelerate the development of new antibody therapeutics and provide guidance for the rational design of next-generation vaccines. 

/pdf/broadly-neutralizing-antibodies-to-sars-cov-2-and-other-1jzut2w1.pdf

Broadly neutralizing antibodies to SARS-CoV-2 and other human coronaviruses

The eukaryotic RNA exosome is an essential and conserved protein complex that can degrade or process RNA substrates in the 3'-to-5' direction. Since its discovery nearly two decades ago, studies have focused on determining how the exosome, along with associated cofactors, achieves the demanding task of targeting particular RNAs for degradation and/or processing in both the nucleus and cytoplasm. In this review, we highlight recent advances that have illuminated roles for the RNA exosome and its cofactors in specific biological pathways, alongside studies that attempted to dissect these activities through structural and biochemical characterization of nuclear and cytoplasmic RNA exosome complexes.

/pdf/targeting-rna-for-processing-or-destruction-by-the-4gs2zgqtma.pdf

Targeting RNA for processing or destruction by the eukaryotic RNA exosome and its cofactors

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1002/1873-3468.12682

Comparison of preribosomal RNA processing pathways in yeast, plant and human cells - focus on coordinated action of endo- and exoribonucleases

https://www.nature.com/articles/s41577-022-00809-x.pdf

The impact of pre-existing cross-reactive immunity on SARS-CoV-2 infection and vaccine responses

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters elicit plasma-neutralizing antibodies against Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5, and that breakthrough infections, but not vaccination alone, induce neutralizing antibodies in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains, whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months after infection. Although most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant–neutralizing antibody that is a strong candidate for clinical development. Description Defending against Omicron The Omicron BA.1 lineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2021 and quickly became dominant, in part because of a large number of mutations that allowed escape from existing antibodies. New infection waves have come from other Omicron sublineages. Park et al. found that either a vaccination booster or a breakthrough infection elicits neutralization activity against the Omicron variants, but only a breakthrough infection induces an antibody response in the nasal mucosa, which might give better protection against transmission. Testing a panel of antibodies, the authors showed that the antibody S2X324 potently neutralizes all SARS-CoV-2 variants tested, making it a candidate for therapeutic development. A cryo–electron microscopy structure shows how this antibody accommodates Omicron-specific mutations to block binding of the viral spike protein to the human ACE2 receptor across the variants. —VV Vaccine boosters or breakthrough infections elicit plasma-neutralizing activity against Omicron variants.

/pdf/imprinted-antibody-responses-against-sars-cov-2-omicron-2de7vqti.pdf

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

The coronavirus spike glycoprotein attaches to host receptors and mediates viral fusion. Using a broad screening approach, we isolated seven monoclonal antibodies (mAbs) that bind to all human-infecting coronavirus spike proteins from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune donors. These mAbs recognize the fusion peptide and acquire affinity and breadth through somatic mutations. Despite targeting a conserved motif, only some mAbs show broad neutralizing activity in vitro against alpha- and betacoronaviruses, including animal coronaviruses WIV-1 and PDF-2180. Two selected mAbs also neutralize Omicron BA.1 and BA.2 authentic viruses and reduce viral burden and pathology in vivo. Structural and functional analyses showed that the fusion peptide–specific mAbs bound with different modalities to a cryptic epitope hidden in prefusion stabilized spike, which became exposed upon binding of angiotensin-converting enzyme 2 (ACE2) or ACE2-mimicking mAbs. Description Blocking a range of coronaviruses Seven coronaviruses cause human disease, and three have caused serious outbreaks in the past 20 years. The potential for future coronavirus outbreaks in humans and the ongoing resistance of severe acute syndrome coronavirus 2 (SARS-CoV-2) variants to existing antibodies make it important to identify cross-reactive antibodies that can be the basis of therapeutics and can guide vaccine design. Low et al. and Dacon et al. isolated antibodies from convalescent individuals that show broad neutralizing activity against a range of coronaviruses, including Omicron variants of SARS-CoV-2. The antibodies target a conserved region of the viral spike protein known as the fusion peptide and may act by preventing the cell fusion that is required for infection of new host cells. —VV A class of broadly reactive antibodies target a cryptic fusion peptide epitope exposed upon coronavirus spike protein binding to ACE2.

/pdf/ace2-binding-exposes-the-sars-cov-2-fusion-peptide-to-1l7zmmaj.pdf

ACE2-binding exposes the SARS-CoV-2 fusion peptide to broadly neutralizing coronavirus antibodies

Mtr4 is a conserved Ski2-like RNA helicase and a subunit of the TRAMP complex that activates exosome-mediated 3′-5′ turnover in nuclear RNA surveillance and processing pathways. Prominent features of the Mtr4 structure include a four-domain ring-like helicase core and a large arch domain that spans the core. The ‘ratchet helix’ is positioned to interact with RNA substrates as they move through the helicase. However, the contribution of the ratchet helix in Mtr4 activity is poorly understood. Here we show that strict conservation along the ratchet helix is particularly extensive for Ski2-like RNA helicases compared to related helicases. Mutation of residues along the ratchet helix alters in vitro activity in Mtr4 and TRAMP and causes slow growth phenotypes in vivo. We also identify a residue on the ratchet helix that influences Mtr4 affinity for polyadenylated substrates. Previous work indicated that deletion of the arch domain has minimal effect on Mtr4 unwinding activity. We now show that combining the arch deletion with ratchet helix mutations abolishes helicase activity and produces a lethal in vivo phenotype. These studies demonstrate that the ratchet helix modulates helicase activity and suggest that the arch domain plays a previously unrecognized role in unwinding substrates.

/pdf/the-mtr4-ratchet-helix-and-arch-domain-both-function-to-1h4qayelkq.pdf

The Mtr4 ratchet helix and arch domain both function to promote RNA unwinding

Creating designer molecules using a combination of select domains from polyketide synthases and/or nonribosomal peptide synthetases (NRPS) continues to be a synthetic goal. However, an incomplete understanding of how protein-protein interactions and dynamics affect each of the domain functions stands as a major obstacle in the field. Of particular interest is understanding the basis for a class of methyltransferase domains (MT) that are found embedded within the adenylation domain (A) of fungal NRPS systems instead of in an end-to-end architecture. The MT domain from bassianolide synthetase (BSLS) was removed and the truncated enzyme BSLS-ΔMT was recombinantly expressed. The biosynthesis of bassianolide was abolished and N-desmethylbassianolide was produced in low yields. Co-expression of BSLS-ΔMT with standalone MT did not recover bassianolide biosynthesis. In order to address the functional implications of the protein insertion, we characterized the N-methyltransferase activity of the MT domain as both the isolated domain (MTBSLS) and as part of the full NRPS megaenzyme. Surprisingly, the MTBSLS construct demonstrated a relaxed substrate specificity and preferentially methylated an amino acid (L-Phe-SNAC) that is rarely incorporated into the final product. By testing the preference of a series of MT constructs (BSLS, MTBSLS, cMT, XLcMT, and aMT) to L-Phe-SNAC and L-Leu-SNAC, we further showed that restricting and/or fixing the termini of the MTBSLS by crosslinking or embedding the MT within an A domain narrowed the substrate specificity of the methyltransferase toward L-Leu-SNAC, the preferred substrate for the BSLS megaenzyme. The embedding of MT into the A2 domain of BSLS is not required for the product assembly, but is critical for the overall yields of the final products. The substrate specificity of MT is significantly affected by the protein context within which it is present. While A domains are known to be responsible for selecting and activating the biosynthetic precursors for NRPS systems, our results suggest that embedding the MT acts as a secondary gatekeeper for the assembly line. This work thus provides new insights into the embedded MT domain in NRPSs, which will facilitate further engineering of this type of biosynthetic machinery to create structural diversity in natural products.

/pdf/modified-substrate-specificity-of-a-methyltransferase-domain-355k62ulh4.pdf

Modified substrate specificity of a methyltransferase domain by protein insertion into an adenylation domain of the bassianolide synthetase.

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ACE2-binding exposes the SARS-CoV-2 fusion peptide to broadly neutralizing coronavirus antibodies

The Mtr4 ratchet helix and arch domain both function to promote RNA unwinding

Modified substrate specificity of a methyltransferase domain by protein insertion into an adenylation domain of the bassianolide synthetase.