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J Mol Biol. 2014 May 15;426(10):2082-97. doi: 10.1016/j.jmb.2014.03.006. Epub 2014 Mar 17.

Intrinsic disorder mediates cooperative signal transduction in STIM1.

Author information

1
Nanobiology Laboratories, Protonic NanoMachine Group, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan.
2
Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan; Quantitative Immunology Research Unit, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
3
Laboratory of Advanced Protein Characterization, Research Center for State-of-the-Art Functional Protein Analysis, Institute for Protein Research, Osaka University, Osaka 565-0871, Japan.
4
Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
5
Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
6
Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan; Research School of Chemistry, Australian National University Section on Biophysical Chemistry, Acton, 0200 ACT, Australia.
7
Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
8
Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
9
Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. Electronic address: standley@ifrec.osaka-u.ac.jp.

Abstract

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 Ca(2+) concentration. The oligomerization of STIM1, which triggers extracellular Ca(2+) 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 Ca(2+) concentration using mathematical modeling based on in vitro experiments. We find that the EF-SAM domain partially unfolds and dimerizes cooperatively with respect to Ca(2+) 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 Ca(2+) loss effectively acts as a denaturant, enabling cooperative dimerization and robust signal transduction. We present a structural model of the Ca(2+)-unbound EF-SAM domain that is consistent with a wide range of evidence, including resistance to proteolytic cleavage of the putative dimerization portion.

KEYWORDS:

STIM1; cooperativity; intrinsic disorder; store-operated calcium entry

PMID:
24650897
DOI:
10.1016/j.jmb.2014.03.006
[Indexed for MEDLINE]
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