Journal
SCIENCE ADVANCES
Volume 6, Issue 12, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.aaz0981
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Funding
- Stiftelsen Olle Engkvist Byggmastare [2015/768]
- IWT doctoral scholarship by Agentschap Innoveren & Ondernemen (VLAIO)
- Lundbeck Foundation through the BRAINSTRUC center [R328-2019-546]
- Lundbeck Foundation through DANDRITE center [R248-2016-2518]
- Swedish Research Council [2016-03610]
- Marie Curie Career Integration Grant [FP7-MC-CIG-618558]
- Magnus Bergvalls Stiftelse [2016-01593]
- Ake Wibergs Stiftelse [M16-0164]
- Swedish National Infrastructure for Computing (SNIC) through the High-Performance Computing Center North (HPC2N) [SNIC 2018/2-32]
- William Harvey International Translational Research Academy
- European Union [608765]
- Swedish Research Council [2016-03610] Funding Source: Swedish Research Council
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Sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) transporters regulate calcium signaling by active calcium ion reuptake to internal stores. Structural transitions associated with transport have been characterized by x-ray crystallography, but critical intermediates involved in the accessibility switch across the membrane are missing. We combined time-resolved x-ray solution scattering (TR-XSS) experiments and molecular dynamics (MD) simulations for real-time tracking of concerted SERCA reaction cycle dynamics in the native membrane. The equilibrium [Ca-2] E1 state before laser activation differed in the domain arrangement compared with crystal structures, and following laser-induced release of caged ATP, a 1.5-ms intermediate was formed that showed closure of the cytoplasmic domains typical of E1 states with bound Ca2+ and ATP. A subsequent 13-ms transient state showed a previously unresolved actuator (A) domain arrangement that exposed the ADP-binding site after phosphorylation. Hence, the obtained TR-XSS models determine the relative timing of so-far elusive domain rearrangements in a native environment.
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