Medizinische Universität Graz - Research portal

Go directly to the nagivation.
Go directly to the content.

Selected Publication:

SHR Neuro Cancer Cardio Lipid Metab Microb

Sallinger, M; Humer, C; Ong, HL; Narayanasamy, S; Lin, QT; Fahrner, M; Grabmayr, H; Berlansky, S; Choi, S; Schmidt, T; Maltan, L; Atzgerstorfer, L; Niederwieser, M; Frischauf, I; Romanin, C; Stathopulos, PB; Ambudkar, I; Leitner, R; Bonhenry, D; Schindl, R.
Essential role of N-terminal SAM regions in STIM1 multimerization and function.
Proc Natl Acad Sci U S A. 2024; 121(21): e2318874121 Doi: 10.1073/pnas.2318874121 [OPEN ACCESS]
Web of Science PubMed FullText FullText_MUG

Leading authors Med Uni Graz: Schindl Rainer
Co-authors Med Uni Graz: Leitner Romana; Schmidt Tony
Altmetrics:
Dimensions Citations:
Plum Analytics:
Scite (citation analytics):
Abstract:: The single-pass transmembrane protein Stromal Interaction Molecule 1 (STIM1), located in the endoplasmic reticulum (ER) membrane, possesses two main functions: It senses the ER-Ca²⁺ concentration and directly binds to the store-operated Ca²⁺ channel Orai1 for its activation when Ca²⁺ recedes. At high resting ER-Ca²⁺ concentration, the ER-luminal STIM1 domain is kept monomeric but undergoes di/multimerization once stores are depleted. Luminal STIM1 multimerization is essential to unleash the STIM C-terminal binding site for Orai1 channels. However, structural basis of the luminal association sites has so far been elusive. Here, we employed molecular dynamics (MD) simulations and identified two essential di/multimerization segments, the α7 and the adjacent region near the α9-helix in the sterile alpha motif (SAM) domain. Based on MD results, we targeted the two STIM1 SAM domains by engineering point mutations. These mutations interfered with higher-order multimerization of ER-luminal fragments in biochemical assays and puncta formation in live-cell experiments upon Ca²⁺ store depletion. The STIM1 multimerization impeded mutants significantly reduced Ca²⁺ entry via Orai1, decreasing the Ca²⁺ oscillation frequency as well as store-operated Ca²⁺ entry. Combination of the ER-luminal STIM1 multimerization mutations with gain of function mutations and coexpression of Orai1 partially ameliorated functional defects. Our data point to a hydrophobicity-driven binding within the ER-luminal STIM1 multimer that needs to switch between resting monomeric and activated multimeric state. Altogether, these data reveal that interactions between SAM domains of STIM1 monomers are critical for multimerization and activation of the protein.
Find related publications in this database (using NLM MeSH Indexing): Stromal Interaction Molecule 1 - metabolism, genetics, chemistry; Humans - administration & dosage; Protein Multimerization - administration & dosage; Neoplasm Proteins - metabolism, genetics, chemistry; Molecular Dynamics Simulation - administration & dosage; Endoplasmic Reticulum - metabolism; Calcium - metabolism; ORAI1 Protein - metabolism, genetics, chemistry; Protein Domains - administration & dosage; HEK293 Cells - administration & dosage; Binding Sites - administration & dosage; Protein Binding - administration & dosage
Find related publications in this database (Keywords): STIM; EF-SAM; SOCE; Orai

Medizinische Universität Graz - Research portal

Navigation/Search

"Faces" of the day:

Selected Publication: