Sequential activation of STIM1 links Ca2+ with luminal domain unfolding

0520315 - MBÚ 2020 RIV US eng J - Journal Article
Schober, R. - Bonhenry, Daniel - Lunz, V. - Zhu, J. - Křížová, A. - Frischauf, I. - Fahrner, M. - Zhang, M.Q. - Waldherr, L. - Schmidt, T. - Derler, I. - Stathopulos, P.B. - Romanin, C. - Ettrich, Rüdiger - Schindel, R.
Sequential activation of STIM1 links Ca2+ with luminal domain unfolding.
Science Signaling. Roč. 12, č. 608 (2019), č. článku eaax3194. ISSN 1945-0877. E-ISSN 1937-9145
R&D Projects: GA MŠMT(CZ) LM2015055; GA ČR(CZ) GJ19-20728Y
Research Infrastructure: C4SYS - 90055
Institutional support: RVO:61388971
Keywords : stromal interaction molecule-1 * calcium sensors * binding-sites
OECD category: Biophysics
Impact factor: 6.467, year: 2019
Method of publishing: Limited access
https://stke.sciencemag.org/content/12/608/eaax3194

The stromal interaction molecule 1 (STIM1) has two important functions, Ca2+ sensing within the endoplasmic reticulum and activation of the store-operated Ca2+ channel Orai1, enabling plasma-membrane Ca2+ influx. We combined molecular dynamics (MD) simulations with live-cell recordings and determined the sequential Ca2+-dependent conformations of the luminal STIM1 domain upon activation. Furthermore, we identified the residues within the canonical and noncanonical EF-hand domains that can bind to multiple Ca2+ ions. In MD simulations, a single Ca 2+ ion was sufficient to stabilize the luminal STIM1 complex. Ca2+ store depletion destabilized the two EF hands, triggering disassembly of the hydrophobic cleft that they form together with the stable SAM domain. Point mutations associated with tubular aggregate myopathy or cancer that targeted the canonical EF hand, and the hydrophobic cleft yielded constitutively clustered STIM1, which was associated with activation of Ca2+ entry through Orai1 channels. On the basis of our results, we present a model of STIM1 Ca2+ binding and refine the currently known initial steps of STIM1 activation on a molecular level.
Permanent Link: http://hdl.handle.net/11104/0305011