Abstract
In allergic disease, mast cell activation is conventionally triggered by allergen-mediated cross-linking of receptor-bound IgE on the cell surface. In addition to its diverse range of intracellular roles in apoptosis, cell proliferation and cancer, Histamine-Releasing Factor (HRF) also activates mast cells and basophils. A subset of IgE antibodies bind HRF through their Fab regions, and two IgE binding sites on HRF have been mapped. HRF can form dimers, and a disulphide-linked dimer is critical for activity. The current model for the activity of HRF in mast cell activation involves cross-linking of receptor-bound IgE by dimeric HRF, mediated by HRF/Fab interactions. HRF crystal and solution structures have provided little insight into either the formation of disulphide-linked HRF dimers or the ability of HRF to activate mast cells. We report the first crystal structure of murine HRF (mHRF) to 4.0Å resolution, revealing a conserved fold. We also solved the structure of human HRF (hHRF) in two new crystal forms, one at the highest resolution (1.4Å) yet reported. The high resolution hHRF structure reveals a disulphide-linked dimer, in which the two molecules are closely associated, and provides a model for the role of both human and murine HRF in mast cell activation.
Highlights
Histamine-Releasing Factor (HRF), referred to as Translationally Controlled Tumour Protein (TCTP), p21, p23 and fortilin, is ubiquitously expressed in eukaryotes, and involved in apoptosis, cell cycle progression, cell proliferation and cancer (Bommer and Thiele, 2004; Nagano-Ito and Ichikawa, 2012; Bommer, 2012)
HRF can form dimers (Yoon et al, 2000; Kim et al, 2009; Kashiwakura et al, 2012), and a disulphide-linked dimer was shown to be crucial for the cytokine-like activity of rat HRF (Kim et al, 2009). murine HRF (mHRF), human HRF (hHRF) and rat HRF contain two cysteine residues, at positions 28 and 172, and Cys172 is suggested to be the site of the intermolecular disulphide bond (Kim et al, 2009)
We report here the first crystal structure of mHRF at 4.0 Å resolution, and two structures of hHRF in new crystal forms, the latter revealing a disulphide-linked dimer
Summary
Histamine-Releasing Factor (HRF), referred to as Translationally Controlled Tumour Protein (TCTP), p21, p23 and fortilin, is ubiquitously expressed in eukaryotes, and involved in apoptosis, cell cycle progression, cell proliferation and cancer (Bommer and Thiele, 2004; Nagano-Ito and Ichikawa, 2012; Bommer, 2012). MHRF, hHRF and rat HRF contain two cysteine residues, at positions 28 and 172, and Cys172 is suggested to be the site of the intermolecular disulphide bond (Kim et al, 2009). The current model for the activity of HRF in mast cell activation involves cross-linking of FcεRI-bound IgE by dimeric HRF, mediated by interactions between HRF and the Fab regions of IgE (Kawakami et al, 2014). Crystal structures for HRF from Plasmodium knowlesi (Vedadi et al, 2007) and Plasmodium falciparum (Eichhorn et al, 2013) contain monomers in their asymmetric units; both proteins contain a cysteine residue which is buried and incapable of forming a disulphide-linked dimer. The solution structure of HRF from Schizosaccharomyces pombe
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