Structural dynamics of Na+ and Ca2+ interactions with full-size mammalian NCX

0585589 - MBÚ 2025 RIV GB eng J - Journal Article
Giladi, M. - Fojtík, Lukáš - Strauss, T. - Da'adoosh, B. - Hiller, R. - Man, Petr - Khananshvili, D.
Structural dynamics of Na+ and Ca2+ interactions with full-size mammalian NCX.
Communications Biology. Roč. 7, č. 1 (2024), č. článku 463. E-ISSN 2399-3642
R&D Projects: GA MŠMT(CZ) EH22_008/0004624; GA MŠMT(CZ) EF18_046/0015974
EU Projects: European Commission(XE) 731077 - EU_FT-ICR_MS
Research Infrastructure: CIISB III - 90242
Institutional support: RVO:61388971
Keywords : sodium-calcium exchanger * cardiac na+-ca2+ exchanger * na+/ca2+ exchanger * splice variants * molecular determinants * equilibrium properties * mass spectrometry * binding domains * ion-exchange * mechanism
OECD category: Biochemistry and molecular biology
Impact factor: 5.9, year: 2022
Method of publishing: Open access
https://www.nature.com/articles/s42003-024-06159-9

Cytosolic Ca2+ and Na+ allosterically regulate Na+/Ca2+ exchanger (NCX) proteins to vary the NCX-mediated Ca2+ entry/exit rates in diverse cell types. To resolve the structure-based dynamic mechanisms underlying the ion-dependent allosteric regulation in mammalian NCXs, we analyze the apo, Ca2+, and Na+-bound species of the brain NCX1.4 variant using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics (MD) simulations. Ca2+ binding to the cytosolic regulatory domains (CBD1 and CBD2) rigidifies the intracellular regulatory loop (5L6) and promotes its interaction with the membrane domains. Either Na+ or Ca2+ stabilizes the intracellular portions of transmembrane helices TM3, TM4, TM9, TM10, and their connecting loops (3L4 and 9L10), thereby exposing previously unappreciated regulatory sites. Ca2+ or Na+ also rigidifies the palmitoylation domain (TMH2), and neighboring TM1/TM6 bundle, thereby uncovering a structural entity for modulating the ion transport rates. The present analysis provides new structure-dynamic clues underlying the regulatory diversity among tissue-specific NCX variants.
Permanent Link: https://hdl.handle.net/11104/0353313