Institute of
bioorganic chemistry

Microbial rhodopsins are integral membrane proteins that contain the retinal chromophore and perform light-dependent ion transport or other functions. The interest in them is largely explained by the perspectives for use in optogenetics in order to regulate the neuronal activity, including for the treatment of various diseases. A team of scientists from the Laboratory of protein engineering and the Group of nanobioengineering of the ICBh RAS has been studying the rhodopsin from Exiguobacterium sibiricum (ESR) for many years. The presence of a lysine residue at position 96 corresponding to the internal proton donor for the Schiff base distinguishes it from bacteriorhodopsin (BR), the most studied retinal protein. In a new study, carried out in collaboration with colleagues from other Russian and foreign institutions, authors have shown that Asp or Glu residues in this position effectively perform the function of a donor in the ESR molecule. However, the kinetics of the photocycle and charge transfer in mutants differ significantly from BR, indicating an alternative mechanism for reprotonation of the Schiff base in ESR. The results are published in the J Photochem Photobiol B.

Pancreatic ductal adenocarcinoma is one of the most lethal cancers worldwide. It is hypothesized that the high level of pancreatic developmental factor SOX9 is necessary for the formation and maintenance of tumor phenotypes. Here authors showed that SOX9 downregulation leads to cell-specific changes in the expression levels of epithelial and mesenchymal protein markers and pancreatic developmental master genes. siSOX9 transfection led to a significant decrease in proliferative activity and to the activation of proapoptotic caspases in transfected cells. The acquired results demonstrate that the SOX9 protein exerts its multiple functions as a pleiotropic regulator of differentiation and a potential promoter of tumor growth. The research was performed at the Laboratory of human genes structure and functions and the Group of gene immuno-oncotherapy of the IBCh RAS and was published in Biomedicines journal.

ADGRL1 (Latrophilin 1), a receptor for α-latrotoxin from the black widow spider, can modulate neurotransmitter release in neurons, but so far no data directly linked it to a heritable condition. A team of scientists from the Laboratory of microfluidic technologies for biomedicine IBCh RAS in collaboration with colleagues from other Russian and foreign institutions showed that individuals heterozygous for different pathogenic variants of ADGRL1 display various neuro-psychiatric features, including developmental delay, intellectual disability, attention deficit/hyperactivity, autism spectrum disorders and epilepsy. In vitro, these pathogenic variants encode receptors with perturbed functions. Adgrl1 knockout mice have altered neurotransmitter release and deficient synapse formation in culture, and show neurological and developmental abnormalities similar to human conditions. The data demonstrate that ADGRL1 haploinsufficiency causes developmental, neurological and behavioral abnormalities in mice and humans, clearly linking ADGRL1 receptor to important CNS functions. The results are publushed in the American Journal of Human Genetics.

Scientists from the Laboratory of biomolecular modeling IBCh authors contributed to a study of a single-pass membrane receptor FIBCD1 and its role in neurodevelopmental disorders. This receptor has a high expression level in the brain and its function in the central nervous system was unknown before. It was shown that FIBCD1 as an endocytic receptor for sulfated glycosaminoglycans in the brain extracellular matrix and a novel gene associated with neurodevelopmental disorders, revealing a critical role in nervous system plasticity. Structural aspects of the study includes an original ligand docking framework of the Laboratory, molecular dynamic simulations, homology modeling and AlphaFold structure prediction. The study is published in EMBO Molecular Medicine (IF 14.2)

Vaccination protects against COVID-19 via the spike protein receptor-binding domain (RBD)-specific antibody formation, but it also affects the innate immunity. In the present study, the team of scientists from the Laboratory of cell interactions IBCh RAS in collaboration with the colleagues from MIPT demonstrated that RBD-coated 100 nm particles induced neutrophil activation after the application to the airways of mice with in advance induced RBD-specific antibodies. In these mice, the portion of mature neutrophils was elevated in the circulating neutrophil population. These neutrophils demonstrated decreased ability of neutrophil extracellular traps (NETs) formation compared to the neutrophils from control mice. Thus, the induction of RBD-specific antibodies stimulates the activation of mature neutrophils that react to RBD-coated particles without triggering excessive inflammation. The study was supported RFBR 20-04-60311 and published in the International Journal of Molecular Sciences.