title: Intrinsic disorder mediates cooperative signal transduction in STIM1.
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.
authors.affiliation: Nanobiology Laboratories, Protonic NanoMachine Group, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Furukawa
authors.affiliation: 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.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Teraguchi
authors.affiliation: 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.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Ikegami
authors.affiliation: Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Onur
authors.initials: O
authors.lastname: Dagliyan
authors.affiliation: Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
authors.forename: Lin
authors.initials: L
authors.lastname: Jin
authors.affiliation: 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.
authors.forename: Damien
authors.initials: D
authors.lastname: Hall
authors.affiliation: Department of Biochemistry and Biophysics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Dokholyan
authors.affiliation: Nanobiology Laboratories, Protonic NanoMachine Group, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Namba
authors.affiliation: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.affiliation: Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kurosaki
authors.affiliation: Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Baba
authors.affiliation: Laboratory of Systems Immunology, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. Electronic address: standley@ifrec.osaka-u.ac.jp.
authors.forename: Daron M
authors.initials: DM
authors.lastname: Standley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017510:Protein Folding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D059748:Proteolysis; D015398:Signal Transduction; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D008562:Membrane Glycoproteins; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D002118:Calcium
keywords: STIM1; cooperativity; intrinsic disorder; store-operated calcium entry