Gideon Schreiber Lab

Protein-Protein Interaction

Research

My laboratory is engaged in understanding the intricate web of protein-protein interactions that underpin every aspect of living organisms. With a sharp focus on the structural and functional nuances of these interactions, our research unravels the molecular dialogue that governs biological signaling. We employ a multifaceted, interdisciplinary strategy that seamlessly integrates protein engineering and bioinformatics. These tools act as pivotal inputs to address complex biological queries. Among our key research themes is a comprehensive elucidation of the interferon signaling pathway—a crucial component of immune response. Moreover, we engaged in tracking the evolutionary journey of the SARS-CoV-2 virus, providing vital insights into pandemic progression and viral behavior. Our most recent endeavor involves the pioneering design of specialized exosomes. These are engineered with precision to transport RNA molecules, opening new vistas in the realm of therapeutic delivery systems. Each discovery propels us closer to decoding the language of life's molecular machinery, which brings us closer to treat diseases in a specific manner.

Research page

Cytokine signaling as a cascade of protein interactions for multiple outputs

Structure/function & evolution of protein interactions towards drug design

Targeted delivery of RNA using engineered exosomes

Investigate the role of interferons in CLL and Melanoma in mouse models

Selected Publications

Structure–function of type I and III interferons

de Weerd N. A., Kurowska A. K., Mendoza J. L. & Schreiber G. (2024) Current Opinion in Immunology. 86, 102413.

Type I and type III interferons (IFNs) are major components in activating the innate immune response. Common to both are two distinct receptor chains (IFNAR1/IFNAR2 and IFNLR1/IL10R2), which form ternary complexes upon binding their respective ligands. This results in close proximity of the intracellularly associated kinases JAK1 and TYK2, which cross phosphorylate each other, the associated receptor chains, and signal transducer and activator of transcriptions, with the latter activating IFN-stimulated genes. While there are clear similarities in the biological responses toward type I and type III IFNs, differences have been found in their tropism, tuning of activity, and induction of the immune response. Here, we focus on how these differences are embedded in the structure/function relations of these two systems in light of the recent progress that provides in-depth information on the structural assembly of these receptors and their functional implications and how these differ between the mouse and human systems.

Virological characteristics of the SARS-CoV-2 XBB variant derived from recombination of two Omicron subvariants

Tamura T., Ito J., Uriu K., Zahradnik J., Kida I., Anraku Y., Nasser H., Shofa M., Oda Y., Lytras S., Nao N., Itakura Y., Deguchi S., Suzuki R., Wang L., Begum M. M., Kita S., Yajima H., Sasaki J. & Schreiber G. (2023) Nature Communications. 14, 1, 2800.

In late 2022, SARS-CoV-2 Omicron subvariants have become highly diversified, and XBB is spreading rapidly around the world. Our phylogenetic analyses suggested that XBB emerged through the recombination of two cocirculating BA.2 lineages, BJ.1 and BM.1.1.1 (a progeny of BA.2.75), during the summer of 2022. XBB.1 is the variant most profoundly resistant to BA.2/5 breakthrough infection sera to date and is more fusogenic than BA.2.75. The recombination breakpoint is located in the receptor-binding domain of spike, and each region of the recombinant spike confers immune evasion and increases fusogenicity. We further provide the structural basis for the interaction between XBB.1 spike and human ACE2. Finally, the intrinsic pathogenicity of XBB.1 in male hamsters is comparable to or even lower than that of BA.2.75. Our multiscale investigation provides evidence suggesting that XBB is the first observed SARS-CoV-2 variant to increase its fitness through recombination rather than substitutions.

Convergent evolution of SARS-CoV-2 Omicron subvariants leading to the emergence of BQ.1.1 variant

Ito J., Suzuki R., Uriu K., Itakura Y., Zahradnik J., Kimura K. T., Deguchi S., Wang L., Lytras S., Tamura T., Kida I., Nasser H., Shofa M., Begum M. M., Tsuda M., Oda Y., Suzuki T., Sasaki J., Sasaki-Tabata K. & Schreiber G. (2023) Nature Communications. 14, 1, 2671.

In late 2022, various Omicron subvariants emerged and cocirculated worldwide. These variants convergently acquired amino acid substitutions at critical residues in the spike protein, including residues R346, K444, L452, N460, and F486. Here, we characterize the convergent evolution of Omicron subvariants and the properties of one recent lineage of concern, BQ.1.1. Our phylogenetic analysis suggests that these five substitutions are recurrently acquired, particularly in younger Omicron lineages. Epidemic dynamics modelling suggests that the five substitutions increase viral fitness, and a large proportion of the fitness variation within Omicron lineages can be explained by these substitutions. Compared to BA.5, BQ.1.1 evades breakthrough BA.2 and BA.5 infection sera more efficiently, as demonstrated by neutralization assays. The pathogenicity of BQ.1.1 in hamsters is lower than that of BA.5. Our multiscale investigations illuminate the evolutionary rules governing the convergent evolution for known Omicron lineages as of 2022.

All Publications