Can the structure of asymmetric arboviruses be resolved through the mapping of their protein interactions?

• Grant number: 24/13116-1
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2024
• End date: September 30, 2029
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Talita Diniz Melo Hanchuk
• Grantee: Talita Diniz Melo Hanchuk
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil

Abstract

The emergence and re-emergence of arthropod-borne viruses, highlight their critical impact on public health. The unpredictable, complex, and dangerous nature of their epidemics requires a multidisciplinary approach for a comprehensive understanding of virus biology. Structural virology provides biological insights into virus vulnerabilities, aiding the development of antiviral strategies, vaccines, and diagnostic. Cryo-electron microscopy (CryoEM) has simplified structural analysis of viruses with helical or icosahedral symmetry. Conversely, pleomorphic viruses stray from high symmetry rules, exhibiting a wide range of sizes and shapes, which impairs structural elucidation. Important human pathogens such as Influenza, Ebola, Sabiá, and Oropouche (OROV) virus, have pleomorphic particles. OROV is the etiological agent of Oropouche fever, responsible for widespread outbreaks in the region of Brazilian Amazon and Latin America. Conventional techniques like X-ray crystallography and CryoEM, may not capture temporary, dynamic, and pleomorphic structures in protein complexes. They rely on well-ordered structural components for high resolution and thus are biased towards repeated biological structures. Crosslink mass spectrometry (XL-MS) offers versatility to explore the structure of pleomorphic viruses determining nearest neighbors and minimal subunit stoichiometry in complexes. XL-MS identifies domain proximity, and intramolecular or intermolecular protein binding sites, offering structural constraints for virion spatial organization modeling. We propose XL-MS as an alternative method for elucidating the structure of asymmetric and pleiomorphic viruses, like OROV, contributing insights into viral organization and to provide new perspectives on systems biology to offer an alternative in the study of emerging asymmetric viruses. Future studies employing multi-omics approaches may uncover further pathogenesis insights, facilitating the development of therapies against these significant public health threats. (AU)