Molecular Basis for Mambalgin-2 Interaction with Heterotrimeric α-ENaC/ASIC1a/γ-ENaC Channels in Cancer Cells.

Autor: Lyukmanova EN; Faculty of Biology, MSU-BIT Shenzhen University, Shenzhen 518172, China.; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, Moscow 117997, Russia.; Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology (National Research University), Institutsky Lane 9, Dolgoprudny, Moscow 141701, Russia.; Interdisciplinary Scientific and Educational School of Moscow University «Molecular Technologies of the Living Systems and Synthetic Biology», Faculty of Biology, Lomonosov Moscow State University, Leninskie Gory, Moscow 119234, Russia., Zaigraev MM; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, Moscow 117997, Russia.; Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology (National Research University), Institutsky Lane 9, Dolgoprudny, Moscow 141701, Russia., Kulbatskii DS; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, Moscow 117997, Russia., Isaev AB; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, Moscow 117997, Russia.; Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology (National Research University), Institutsky Lane 9, Dolgoprudny, Moscow 141701, Russia., Kukushkin ID; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, Moscow 117997, Russia.; Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology (National Research University), Institutsky Lane 9, Dolgoprudny, Moscow 141701, Russia., Bychkov ML; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, Moscow 117997, Russia., Shulepko MA; Faculty of Biology, MSU-BIT Shenzhen University, Shenzhen 518172, China., Chugunov AO; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, Moscow 117997, Russia.; Phystech School of Biological and Medical Physics, Moscow Institute of Physics and Technology (National Research University), Institutsky Lane 9, Dolgoprudny, Moscow 141701, Russia., Kirpichnikov MP; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya 16/10, Moscow 117997, Russia.; Interdisciplinary Scientific and Educational School of Moscow University «Molecular Technologies of the Living Systems and Synthetic Biology», Faculty of Biology, Lomonosov Moscow State University, Leninskie Gory, Moscow 119234, Russia.
Jazyk: angličtina
Zdroj: Toxins [Toxins (Basel)] 2023 Oct 13; Vol. 15 (10). Date of Electronic Publication: 2023 Oct 13.
DOI: 10.3390/toxins15100612
Abstrakt: Cancer progression is characterized by microenvironmental acidification. Tumor cells adapt to low environmental pH by activating acid-sensing trimeric ion channels of the DEG/ENaC family. The α-ENaC/ASIC1a/γ-ENaC heterotrimeric channel is a tumor-specific acid-sensing channel, and its targeting can be considered a new strategy for cancer therapy. Mambalgin-2 from the Dendroaspis polylepis venom inhibits the α-ENaC/ASIC1a/γ-ENaC heterotrimer more effectively than the homotrimeric ASIC1a channel, initially proposed as the target of mambalgin-2. Although the molecular basis of such mambalgin selectivity remained unclear. Here, we built the models of the complexes of mambalgin-2 with the α-ENaC/ASIC1a/γ-ENaC and ASIC1a channels, performed MD and predicted the difference in the binding modes. The importance of the 'head' loop region of mambalgin-2 for the interaction with the hetero-, but not with the homotrimeric channel was confirmed by site-directed mutagenesis and electrophysiology. A new mode of allosteric regulation of the ENaC channels by linking the thumb domain of the ASIC1a subunit with the palm domain of the γ-ENaC subunit was proposed. The data obtained provide new insights into the regulation of various types of acid-sensing ion channels and the development of new strategies for cancer treatment.
Databáze: MEDLINE
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