TY - JOUR
T1 - Intrinsic disorder mediates cooperative signal transduction in STIM1
AU - Furukawa, Yukio
AU - Teraguchi, Shunsuke
AU - Ikegami, Takahisa
AU - Dagliyan, Onur
AU - Jin, Lin
AU - Hall, Damien
AU - Dokholyan, Nikolay
AU - Namba, Keiichi
AU - Akira, Shizuo
AU - Kurosaki, Tomohiro
AU - Baba, Yoshihiro
AU - Standley, Daron M.
N1 - Funding Information:
The authors would like to thank Ms. Yuriko Suenari for her useful advice and Ms. Aya Takamori for help with mass spectrometry measurements. This work was supported by a combined research grant, provided by IFReC to D.M.S. and Y.B., by the Platform for Drug Discovery, Informatics and Structural Life Science , and by the Grant-in-Aid for Scientific Research on Innovative Areas “Harmonized Supramolecular Motility Machinery and Its Diversity” (No. 25117501 ) to Ms. Aya Takamori.
PY - 2014/5/15
Y1 - 2014/5/15
N2 - Intrinsically disordered domains have been reported to play important roles in signal transduction networks by introducing cooperativity into protein-protein interactions. Unlike intrinsically disordered domains that become ordered upon binding, the EF-SAM domain in the stromal interaction molecule (STIM) 1 is distinct in that it is ordered in the monomeric state and partially unfolded in its oligomeric state, with the population of the two states depending on the local Ca2 + concentration. The oligomerization of STIM1, which triggers extracellular Ca2 + influx, exhibits cooperativity with respect to the local endoplasmic reticulum Ca 2 + concentration. Although the physiological importance of the oligomerization reaction is well established, the mechanism of the observed cooperativity is not known. Here, we examine the response of the STIM1 EF-SAM domain to changes in Ca2 + concentration using mathematical modeling based on in vitro experiments. We find that the EF-SAM domain partially unfolds and dimerizes cooperatively with respect to Ca2 + concentration, with Hill coefficients and half-maximal activation concentrations very close to the values observed in vivo for STIM1 redistribution and extracellular Ca 2 + influx. Our mathematical model of the dimerization reaction agrees quantitatively with our analytical ultracentrifugation-based measurements and previously published free energies of unfolding. A simple interpretation of these results is that Ca2 + loss effectively acts as a denaturant, enabling cooperative dimerization and robust signal transduction. We present a structural model of the Ca2 +-unbound EF-SAM domain that is consistent with a wide range of evidence, including resistance to proteolytic cleavage of the putative dimerization portion.
AB - Intrinsically disordered domains have been reported to play important roles in signal transduction networks by introducing cooperativity into protein-protein interactions. Unlike intrinsically disordered domains that become ordered upon binding, the EF-SAM domain in the stromal interaction molecule (STIM) 1 is distinct in that it is ordered in the monomeric state and partially unfolded in its oligomeric state, with the population of the two states depending on the local Ca2 + concentration. The oligomerization of STIM1, which triggers extracellular Ca2 + influx, exhibits cooperativity with respect to the local endoplasmic reticulum Ca 2 + concentration. Although the physiological importance of the oligomerization reaction is well established, the mechanism of the observed cooperativity is not known. Here, we examine the response of the STIM1 EF-SAM domain to changes in Ca2 + concentration using mathematical modeling based on in vitro experiments. We find that the EF-SAM domain partially unfolds and dimerizes cooperatively with respect to Ca2 + concentration, with Hill coefficients and half-maximal activation concentrations very close to the values observed in vivo for STIM1 redistribution and extracellular Ca 2 + influx. Our mathematical model of the dimerization reaction agrees quantitatively with our analytical ultracentrifugation-based measurements and previously published free energies of unfolding. A simple interpretation of these results is that Ca2 + loss effectively acts as a denaturant, enabling cooperative dimerization and robust signal transduction. We present a structural model of the Ca2 +-unbound EF-SAM domain that is consistent with a wide range of evidence, including resistance to proteolytic cleavage of the putative dimerization portion.
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U2 - 10.1016/j.jmb.2014.03.006
DO - 10.1016/j.jmb.2014.03.006
M3 - Article
C2 - 24650897
AN - SCOPUS:84899638075
SN - 0022-2836
VL - 426
SP - 2082
EP - 2097
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 10
ER -