Luminal STIM1 Mutants that Cause Tubular Aggregate Myopathy Promote Autophagic Processes

0533047 - MBÚ 2021 RIV CH eng J - Journal Article
Sallinger, M. - Tiffner, A. - Schmidt, T. - Bonhenry, Daniel - Waldherr, L. - Frischauf, I. - Lunz, V. - Derler, I. - Schober, R. - Schindl, R.
Luminal STIM1 Mutants that Cause Tubular Aggregate Myopathy Promote Autophagic Processes.
International Journal of Molecular Sciences. Roč. 21, č. 12 (2020), č. článku 4410. E-ISSN 1422-0067
R&D Projects: GA ČR(CZ) GJ19-20728Y
Institutional support: RVO:61388971
Keywords : activates crac channels * ca2+ sensor * orai1 * depletion * proteins * tfeb * calcineurin * tubular aggregate myopathy
OECD category: Biochemistry and molecular biology
Impact factor: 5.924, year: 2020
Method of publishing: Open access
https://www.mdpi.com/1422-0067/21/12/4410

Stromal interaction molecule 1 (STIM1) is a ubiquitously expressed Ca(2+)sensor protein that induces permeation of Orai Ca(2+)channels upon endoplasmic reticulum Ca2+-store depletion. A drop in luminal Ca(2+)causes partial unfolding of the N-terminal STIM1 domains and thus initial STIM1 activation. We compared the STIM1 structure upon Ca(2+)depletion from our molecular dynamics (MD) simulations with a recent 2D NMR structure. Simulation- and structure-based results showed unfolding of two alpha-helices in the canonical and in the non-canonical EF-hand. Further, we structurally and functionally evaluated mutations in the non-canonical EF-hand that have been shown to cause tubular aggregate myopathy. We found these mutations to cause full constitutive activation of Ca2+-release-activated Ca(2+)currents (I-CRAC) and to promote autophagic processes. Specifically, heterologously expressed STIM1 mutations in the non-canonical EF-hand promoted translocation of the autophagy transcription factors microphthalmia-associated transcription factor (MITF) and transcription factor EB (TFEB) into the nucleus. These STIM1 mutations additionally stimulated an enhanced production of autophagosomes. In summary, mutations in STIM1 that cause structural unfolding promoted Ca(2+)down-stream activation of autophagic processes.
Permanent Link: http://hdl.handle.net/11104/0311546