Differences in Medium-Induced Conformational Plasticity Presumably Underlie Different Cytotoxic Activity of Ricin and Viscumin
Pavel Volynsky,
Diana Maltseva,
Valentin Tabakmakher,
Eduard V. Bocharov,
Maria Raygorodskaya,
Galina Zakharova,
Elena Britikova,
Alexander Tonevitsky,
Roman Efremov
Affiliations
Pavel Volynsky
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Miklukho-Maklaya Str. 16/10, 117997 Moscow, Russia
Diana Maltseva
International Laboratory of Microphysiological Systems, Faculty of Biology and Biotechnology, National Research University Higher School of Economics, Myasnitskaya ul. 20, 101000 Moscow, Russia
Valentin Tabakmakher
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Miklukho-Maklaya Str. 16/10, 117997 Moscow, Russia
Eduard V. Bocharov
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Miklukho-Maklaya Str. 16/10, 117997 Moscow, Russia
Maria Raygorodskaya
Scientific Research Center Bioclinicum, Ugreshskaya Str. 2/85, 115088 Moscow, Russia
Galina Zakharova
Scientific Research Center Bioclinicum, Ugreshskaya Str. 2/85, 115088 Moscow, Russia
Elena Britikova
Institute of Bioorganic Chemistry NASB, Kuprevich St. 5, 220141 Minsk, Belarus
Alexander Tonevitsky
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Miklukho-Maklaya Str. 16/10, 117997 Moscow, Russia
Roman Efremov
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Miklukho-Maklaya Str. 16/10, 117997 Moscow, Russia
Structurally similar catalytic subunits A of ricin (RTA) and viscumin (MLA) exhibit cytotoxic activity through ribosome inactivation. Ricin is more cytotoxic than viscumin, although the molecular mechanisms behind this difference are still poorly understood. To shed more light on this problem, we used a combined biochemical/molecular modeling approach to assess possible relationships between the activity of toxins and their structural/dynamic properties. Based on bioassay measurements, it was suggested that the differences in activity are associated with the ability of RTA and MLA to undergo structural/hydrophobic rearrangements during trafficking through the endoplasmic reticulum (ER) membrane. Molecular dynamics simulations and surface hydrophobicity mapping of both proteins in different media showed that RTA rearranges its structure in a membrane-like environment much more efficiently than MLA. Their refolded states also drastically differ in terms of hydrophobic organization. We assume that the higher conformational plasticity of RTA is favorable for the ER-mediated translocation pathway, which leads to a higher rate of toxin penetration into the cytoplasm.