Birth of protein folds and functions in the virome
Inventors & their inventions
Axial: https://linktr.ee/axialxyz
Axial partners with great founders and inventors. We invest in early-stage life sciences companies such as Appia Bio, Seranova Bio, Delix Therapeutics, Simcha Therapeutics, among others often when they are no more than an idea. We are fanatical about helping the rare inventor who is compelled to build their own enduring business. If you or someone you know has a great idea or company in life sciences, Axial would be excited to get to know you and possibly invest in your vision and company. We are excited to be in business with you — email us at info@axialvc.com
This research paper explores the vast and largely uncharted territory of viral proteins. The authors focus on eukaryotic viruses, a group exhibiting significant sequence diversity, making traditional homology-based function prediction challenging. To overcome this, they employ a cutting-edge approach: predicting the three-dimensional structures of viral proteins using advanced computational methods and then leveraging these structures for functional insights.
The study begins by assembling a comprehensive database of predicted protein structures from 67,715 proteins encoded by 4,463 eukaryotic viruses. This massive dataset significantly expands the existing structural information on viral proteins, particularly those lacking known homologs in databases like AlphaFold. By clustering these proteins based on both sequence and structural similarity, they identify 18,192 distinct protein clusters, revealing a surprising level of structural diversity within the virome. A significant portion (62%) of the viral proteins in their database are structurally unique, highlighting the immense untapped potential for discovery within the viral world.
The researchers find that while many viral proteins are structurally distinct, a substantial number (38%) exhibit structural similarity to proteins found in other organisms, including humans. This unexpected structural conservation opens doors to functional annotation. By comparing viral protein structures to those of known function, they predict functions for approximately 25% of previously unannotated viral proteins. These predictions span various functional categories, with particular emphasis on those involved in immune evasion.
One particularly intriguing discovery involves a widespread class of enzymes called RNA ligase T (LigT)-like phosphodiesterases (PDEs). These enzymes are found across bacterial and eukaryotic viruses, exhibiting remarkable structural conservation despite significant sequence divergence. The authors experimentally validate the function of LigT homologs encoded by avian poxviruses, demonstrating their ability to hydrolyze cyclic GMP-AMP (cGAMP), a key molecule in the host's innate immune response. This finding reveals a conserved mechanism of immune evasion employed by viruses across vastly different taxonomic groups, underlining the evolutionary significance of this enzyme family.
The study further expands on the value of structural comparisons by analyzing similarities between viral proteins and non-viral proteins. The researchers identify several examples where viral proteins from human pathogens show striking structural resemblance to host proteins. This highlights the potential for viral proteins to mimic or exploit host cellular functions for their own benefit. Specific examples include structural similarities between:
Poxvirus proteins and mammalian gasdermins: suggesting a possible role in the modulation of pyroptosis, a form of programmed cell death.
Poxvirus proteins and human galactosyltransferase COLGALT1: hinting at a potential mechanism for viral attachment to host cells.
Herpesvirus UL43-like proteins and human equilibrative nucleoside transporters (ENTs): implying a potential role in nucleoside transport, potentially affecting viral replication or host metabolism.
The use of structural information profoundly enhances the identification of protein relationships. By combining sequence and structural clustering, the study demonstrates a substantial increase in the taxonomic diversity of protein clusters compared to relying on sequence information alone. This showcases the power of structural data in uncovering functionally relevant links between proteins with low sequence similarity, particularly important in the rapidly evolving viral world.
The paper also tackles the methodological aspects of their approach, addressing the challenges of protein structure prediction accuracy and the sensitivity of various alignment methods. They present a detailed comparison of sequence-based and structure-based methods for identifying protein similarities, demonstrating the superior performance of structure-based approaches, especially in detecting remote homologs.
In summary, this paper offers a significant advancement in our understanding of the virome. The massive structural database generated provides an unprecedented resource for studying viral proteins, particularly those with unknown functions. The findings highlight the evolutionary strategies used by viruses to exploit host cellular machinery and evade the immune system. The integration of structure-based methods for protein analysis proves exceptionally powerful in bridging the gap between sequence divergence and functional conservation, especially crucial in the study of highly variable viral proteins. The work presents numerous avenues for future research, paving the way for a deeper understanding of viral pathogenesis, evolution, and the development of novel antiviral strategies. The findings related to the widespread presence and activity of LigT-like PDEs across diverse viral lineages underscore the significant potential for the discovery of novel antiviral targets, further emphasizing the considerable impact of this research. Finally, the methodological insights and the robust database generated offer a powerful framework for exploring the vast, largely uncharacterized landscape of viral proteins, establishing a new baseline for future research in virology.
https://www.nature.com/articles/s41586-024-07809-y
