Interaction of S100A13 with C2 domain of receptor for advanced glycation end products (RAGE),☆☆

https://doi.org/10.1016/j.bbapap.2014.06.017Get rights and content

Highlights

  • Understand the S100A13 protein interactions with RAGE receptor.

  • Solution structure of S100A13–RAGE C2 complex.

  • This study provides a proposed mechanism of S100A13 induced apoptosis.

  • This might be the first sign of complex RAGE C2–S100 protein interactions.

Abstract

S100A13 is involved in several key biological functions like angiogenesis, tumor formation and cell apoptosis. It is a homodimeric protein that belongs to the S100 protein family. S100A13 is co-expressed with acidic fibroblast growth factor (FGF1) and interleukin-1α which are key angiogenesis inducers. The S100 proteins have been shown to be involved in several cellular functions such as calcium homeostasis, cell growth and differentiation dynamic of cytoskeleton. Its biological functions are mainly mediated through the receptor for advanced glycation end products (RAGE) signaling. RAGE is involved in inflammatory processes and is associated with diabetic complications, tumor outgrowth, and neurodegenerative disorders. RAGE induces cellular signaling upon binding of different ligands, such as S100 proteins, glycated proteins, and HMGB1. RAGE signaling is complex, and it depends on the cell type and concentration of the ligand. Molecular level interactions of RAGE and S100 proteins are useful to understand the RAGE signaling diversity. In this report we focus on the molecular level interactions of S100A13 and RAGE C2 domain. The binding between RAGE C2 and S100A13 is moderately strong (Kd ~ 1.3 μM). We have solved the solution structure of the S100A13–RAGE C2 complex and pronounce the interface regions in S100A13–RAGE C2 complex which are helpful for drug development of RAGE induced diseases.

Introduction

S100A13 is a homodimeric protein that belongs to the S100 subfamily of EF hand Ca2 +-binding proteins [1], [2], [3]. S100A13 is known to play an important role in tumor formation and angiogenesis [4], [5], [6], [7]. Several members of the S100 gene family are associated with the cytoskeleton. The actin cytoskeleton is essential for transmembrane signaling, endocytosis, and secretion [8]. S100A13 has been reported to co-express with acidic fibroblast growth factor 1 (FGF1) in brain tumors [9] exhibiting a perivascular distribution. S100A13 is a member of the Ca2 +-binding family of proteins, which are characterized by the absence of a classical signal peptide sequence. S100A13 is a unique member of the S100 gene family that codes a highly charged carboxy terminal domain that may be involved in specific protein interactions. Maciag and coworkers showed that S100A13 is involved in the regulation of FGF1 release in response to stress, independent of the conventional ER/Golgi pathway [10], [11]. S100A13 is the only member of the S100 family that has been shown to be involved in the non-classical export of proteins without signal peptides, such as fibroblast growth factors, interleukin 1α and synaptotagmins [12], [13], [14], [15].

The S100 proteins have been shown to bind and to control various proteins involved in several cellular functions such as calcium homeostasis, cell growth, differentiation of the cytoskeleton and energy metabolism. Calcium binding to the EF hand initiates structural changes in the S100 proteins that allow them to interact with target proteins and affect their activity [16], [17].

RAGE is involved in inflammatory processes and is associated with diabetic complications, tumor outgrowth and neurodegenerative disorders [18], [19], [20]. RAGE induces cellular signaling upon binding of different ligands, such as S100 proteins, glycated proteins, amyloid-β and HMGB1 [21], [22], [23]. RAGE signaling plays a central role in the inflammatory response [24], acute, chronic inflammatory disorders [25] and certain cancers [26]. RAGE-mediated transduction pathways can be activated by extracellular S100 proteins and translocation of S100 proteins is inhibited by soluble RAGE [27].

Most studies on extracellular S100 proteins have focused on neurite extension, interactions with RAGE and MAP kinase-related signal transduction pathways [28]. RAGE is a cell surface receptor that binds to ligands with diverse structural features. RAGE contains one extracellular variable domain (V domain), two constant C domains (C1 and C2 domain), a transmembrane domain and a cytosolic tail. RAGE expression has been identified in endothelial cells, monocytes/macrophages, smooth muscle cells and neurons. RAGE signaling is complex and depends on the cell type and on the ligand concentration. RAGE is known to involve in binding with S100A1, S100A2, S100A4, S100A5, S100A6, S100A7, S100A8/A9, S100A11, S100A12, S100A13 and S100P [29]. Based on the current literature, binding between the S100 proteins and the RAGE V or C2 domain induces cell proliferation or cell apoptosis, respectively [29], [30].

In this study, we solved the solution structure of the S100A13–RAGE C2 complex. We describe the interface regions in the S100A13–RAGE C2 complex, which may be helpful for drug development against RAGE induced disorders. Our results demonstrate that S100A13 and RAGE C2 domain binding is mainly driven by hydrophobic and charge–charge interactions.

Section snippets

Reagents

GST-Sepharose was purchased from Amersham Pharmacia Biotech. Metal affinity sepharose was purchased from Clonetech. 15NH4Cl, labeled glucose (13C) and D2O were purchased from Cambridge Isotope Laboratories. The components for the Luria Broth media were obtained from AMRESCO. Aprotinin, pepstatin, leupeptin, phenylmethylsulfonyl fluoride, TritonX-100 and β-mercaptoethanol were all purchased from Sigma Co. (St. Louis, MO). Centricon and Amicon membranes were purchased from Millipore. All of the

Isothermal titration calorimetry

Isothermal titration calorimetry (ITC) is a very expedient technique to study protein–protein interactions. ITC may be reliably used to measure the binding constants and energy changes that accompany the interactions of proteins with other proteins [49]. ITC measurements provide information on the number of protein binding sites. We determined that the binding affinity (Kd) of RAGE C2 to S100A13 is 1.30 μM (Fig. 1).

The binding isothermogram characterizing the S100A13–RAGE C2 interaction is shown

Discussion

Thermodynamic studies between S100A13 and RAGE C2 domain using isothermal titration calorimetry defined the binding constant (Kd) as 1.3 μM, implying a moderately strong interaction. Size exclusion chromatography is a useful technique to monitor changes in the molecular size of protein complex upon protein–protein interactions. We estimated the molecular size of free S100A13, RAGE C2 domain and RAGE C2–S100A13 complex by size exclusion chromatography. The free S100A13, free RAGE C2 domain and

Acknowledgements

We acknowledge financial support from the National Science Council (NSC) of Taiwan. We would like to thank the 700 MHz Nuclear Magnetic Resonance facility in the Chemistry Department, National Tsing Hua University.

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    This research was supported by an operating grant from the National Science Council, Taiwan (NSC 100-2113-M-007-012-MY3).

    ☆☆

    The atomic coordinates and restraint tables for the RAGE C2–S100A13 tetrameric complex have been deposited in the Protein Data Bank (accession code2le9).

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