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. 2018 Aug 22;3(8):9689–9698. doi: 10.1021/acsomega.8b00922

S100B as an Antagonist To Interfere with the Interface Area Flanked by S100A11 and RAGE V Domain

Deepu Dowarha †, Ruey-Hwang Chou ‡, Chin Yu †,*
PMCID: PMC6644751  PMID: 31459098

Abstract

graphic file with name ao-2018-009225_0009.jpg

The Ca2+-sensing protein S100A11 of the S100 family is an important mediator of numerous biological functions and pathological conditions including cancer. The receptor for advanced glycation end products (RAGE) has been well accepted as the major receptor for several S100 family members. Here, we take the S100B protein as an antagonist to interfere with the interaction flanked by S100A11 and the RAGE V domain. We employed NMR spectroscopy to describe the interactions between the S100A11 and S100B proteins. 1H–15N heteronuclear single-quantum correlation-NMR titrations showed the potential binding dynamics of S100A11 and S100B interactions. In the HADDOCK program, we constructed the S100A11–S100B heterodimer complex that was then superimposed with the S100A11–S100B complex structure in the same orientation as the S100A11–RAGE V domain complex. This overlay analysis showed that S100B could interfere in the binding section of S100A11 and the RAGE V domain. Additionally, water-soluble tetrazolium-1 assay provided a functional read-out of the effects of these proteins in an in vitro cancer model. Our study establishes that the development of an S100B antagonist could perform a vital part in the treatment of S100- and RAGE-dependent human diseases.

Introduction

The name “S100” was given by Moore to the brain-specific proteins later identified as a mixture of S100A1 and S100B protein.1−3 These small, acidic proteins were first referred to as S100 owing to their ability to dissolve completely in 100% saturated ammonium sulfate at pH 7.1 The human S100 family is comprised of 21 similar proteins that are exclusive to vertebrates and includes two discrete EF-hand motifs with a helix–loop–helix structure. S100 family members range from 10 to 12 kDa, exhibit site-specific expression patterns, and efficiently form homo and heterodimers.4−6 These proteins have known interactions with calcium, zinc, and copper ions, and Ca2+ binding enables the numerous intracellular and extracellular regulatory effects of these proteins.7,8 All S100 family members are considered Ca2+-sensing proteins except for S100G, which acts as a Ca2+-modulating protein by buffering cytosolic Ca2+.9 S100 proteins are effective regulators of a variety of diverse task involving Ca2+ homeostasis, transcription, cell proliferation and differentiation, tissue development, and regeneration/repair. They are also involved in the origin and development of chronic inflammation, autoimmunity, contagious ailments, tumors, and their metastases.10

S100 proteins have recently attracted attention due to their involvement in various tumorigenic processes (e.g., tumor progression, metastasis) and altered expression patterns in multiple human cancers (e.g., pancreatic, lung).11−23 S100A11, first identified as Calgizzarin or S100C, was initially extracted from the smooth muscle of chicken gizzards and the cardiac muscle of pigs.24,25 It is expressed in the kidney, heart, lung, and most muscle tissues, with peak levels in the placenta and lowest in the brain.26 S100A11 mediates multiple biological processes by binding with target proteins such as receptor for advanced glycation end products (RAGE), Annexin A1, Annexin A2, p53, and Rad54B.27 However, its oncogenic role in many cancers has drawn the maximum interest.28 It appears to be associated with tumor progression in adenocarcinomas and is expressed excessively in various cancers such as lung,29 colorectal,30 breast,31 pancreatic,32,33 colon,34 laryngeal,35 and papillary thyroid carcinoma.36 Additionally, S100A11 is down-regulated in the bladder37 and ovarian cancer.38

The receptor for advanced glycation end products (RAGE) is a 35 kDa cell surface protein which is the member of the immunoglobulin superfamily. It is comprised of V, C1, and C2 domains reminiscent of 3 Ig-like regions, a transmembrane helix, and a cytoplasmic end respectively that mediates intracellular signaling.39−43 RAGE works as a pattern recognition receptor and thereby associates with a range of signaling molecules such as advanced glycation end products (AGEs), amphoterin, C3a, S100/calgranulin polypeptides, phosphatidylserine, amyloid β, and advanced oxidation protein products.44−50

RAGE binds multiple ligands and has been involved in an array of ailments (such as diabetic complications, cardiovascular disorders, chronic inflammation disorders, Alzheimer disease, and neurodegeneration).51 Furthermore, RAGE activation is linked to multiple cancers including lung,52 colorectal,53 pancreatic,54 kidney,55 prostate,56 ovarian,57 breast,58 and melanoma.59 In recent years, RAGE has emerged as a major receptor for the S100 family proteins, and this S100–RAGE interaction mediates cell migration, invasion, tumor growth, angiogenesis, and metastasis but the mechanism of action remains largely unknown.60−62 Therefore, interaction studies on RAGE and its associated ligands are desired to elucidate more insights into the development of different diseases and design the treatment modalities thereof.

The S100B protein is associated with a multigenic family of small proteins that binds calcium via EF-hand motifs.63,64 It is one of the earliest associates of the S100 protein family to be recognized and is the most active in the head region.3 S100B consists of S100 ββ homodimers.65 Many different cells including astrocytes,66 myoblasts,67 photoreceptor cells,68 skeletal muscle tissue,69 certain neuronal populations,70 oligodendroglial progenitor cells,71 and oligodendrocytes72 express this protein in varying amounts. Calcium-induced S100B exerts its intracellular and extracellular functions by interacting with other proteins. Previous studies have provided evidence of S100B’s involvement in several regulatory pathways concerning cell proliferation, differentiation, and morphology, calcium homeostasis, protein phosphorylation, transcription, microtubule and type III intermediate filament dynamics, enzyme activity, and metabolism.8,9,73,74 Interaction studies pertaining to S100B and RAGE has been performed earlier in detail.41,75,76 Depending on the microenvironment, secreted S100B has been shown to bind to RAGE in neurons, macrophages, myoblasts, astrocytes, and microglia toward carrying out a diversity of biological functions with variable effects (i.e., favorable or deleterious).77

An elevated amount of S100B has been noticed in a range of clinical circumstances such as brain injury and ischemia, neurodegeneration, inflammation, and mental disorders.78 S100B is secreted by glioblastoma cancer cells in vitro.79 Moreover, S100B is a firmly developed predictive indicator for malignant melanoma, and increased serum levels associated with negative patient outcomes.80,81

It was previously reported that S100A11 interacts with the S100B protein.82,83 In this study, we used the S100B protein as a probable candidate for an antagonist to hinder interactions flanked by S100A11 and the RAGE V domain, thereby inhibiting additional signal transduction. By employing the HADDOCK (High Ambiguity Driven protein–protein Docking) program, we constructed an S100A11–S100B heterodimer complex by compiling the data on interacting sites between S100A11 and S100B proteins from heteronuclear single-quantum correlation-NMR (HSQC-NMR) experiments. Then we superimposed the two complex structures (S100A11 and S100B complexes with the S100A11 and RAGE V domain complexes), which illustrated that S100B could interfere at the binding region of S100A11 and the RAGE V domain. Moreover, a water-soluble tetrazolium-1 (WST-1) assay confirmed that the S100B protein can hinder cell proliferation in vitro. This collaborative study provides structural insights into the S100A11–S100B heterodimer complex formation, which will facilitate the discovery of new therapies for S100- and RAGE-mediated diseases.

Results and Discussion

Binding Interface (S100A11/S100B) Region in S100A11

The binding regions among proteins or amongst proteins and their associated ligands are generally recognized by employing 1H–15N HSQC-NMR experiments.84,85 The residues near the S100A11 and S100B interfaces were recognized by analyzing the resonances on the HSQC-NMR spectra of free S100A11 and compared to those of the S100A11–S100B complex.

Figure 1a displays the overlaid HSQC-NMR spectra of only nitrogen-15-labeled S100A11 (red color) and nitrogen-15-labeled S100A11 complexed with unlabeled S100B (blue color). Some of the NMR signals decreased upon the addition of free S100B to nitrogen-15-labeled S100A11. The observed HSQC-NMR indications of the S100A11–S100B complex were significantly inferior to those obtained with free S100A11. This occurrence was owing to 15N nuclei near the interaction spots of the proteins among S100A11 and S100B.

Figure 1.

Figure 1

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Analysis of the binding interface (S100A11/S100B) region in S100A11. (a) 1H–15N HSQC spectra overlay of free 15N S100A11 (red) and 15N S100A11 binding to unlabeled S100B (blue). Cross-peaks illustrating changes in intensities are shown in boxes. Horizontal lines connect the NH2 side chains. (b) The cross-peak intensity plot (I/I0) where (I) denotes the cross-peak intensity of S100A11–S100B complex and (I0) indicates the early intensity of free S100A11 versus a number of amino-acid residues (1–105) illustrated as a bar diagram. (c) A picture illustration of the S100A11 monomer with residues exhibiting decreases in cross-peak signals distinguished by the cyan color.

The 15N nuclei surrounding the interface region were affected by the presence of other proteins in close vicinity, which resulted in lowering the cross-peaks on the HSQC-NMR spectrum. The S100 protein residues were influenced due to the formation of a complex with their target proteins. The 1H–15N HSQC-NMR spectra from the free S100A11 and the S100A11–S100B complex were matched to detect the perturbation or reduction in the intensity of the S100A11 residues near the interface region.

A bar graph that compares the residues from both spectra is shown in Figure 1b. Some residues from the HSQC cross-peaks had considerably inferior intensities (Figure 1b). These S100A11 residues (red color) were G29, N53, G58, and S101. Residues along with the NH2 side chains of asparagines and glutamines (namely Q22, N31, N44, Q54, N70, Q74, N82, and Q102) were also included (as labeled in boxes that are connected by horizontal lines in Figure 1a, however, their specific side-chain assignments were unavailable) for plotting on the three-dimensional (3D) construction of the S100A11 monomer (Figure 1c).

Binding Interface (S100A11/S100B) in S100B

From HSQC-NMR experiments, the spectra of the free nitrogen-15-labeled S100B area were overlaid on the spectra of the nitrogen-15-labeled S100B in the complex with unlabeled S100A11 (Figure 2a).

Figure 2.

Figure 2

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Analysis of the binding interface (S100A11/S100B) region in S100B. (a) 1H–15N HSQC spectra overlay of free 15N S100B (red) and 15N S100B binding to unlabeled S100A11 (blue). Cross-peaks showing changes in intensities are shown in boxes. (b) Cartoon representation of the S100B monomer with residues exhibiting a decrease in cross-peak signals are shown in yellow.

Cross-peaks with reduced intensities (line broadening) were identified and marked including S1, S18, H42, I47, and K48. The S1, S18, H42, I47, and K48 residues (red color) were mapped onto the 3D construction of the S100B monomer protein (Figure 2b).

Fundamental Depiction of the S100A11–S100B Complex

To compute the protein–protein interactions, the basic model of the S100A11–S100B complex was built via the HADDOCK program. The difference in the intensities and the HSQC-NMR spectra information analysis from S100A11 and S100B provided the data for Ambiguous Interaction Constraints (AIRs). As input parameters in HADDOCK, the residues with a difference in the intensities (HSQC-NMR) indicated the constraints for computation. The HADDOCK outcomes produced models for the heterodimeric S100A11–S100B complex. The structure of Ca2+-bound S100A11 was attained from PDB ID: 2LUC and the model of S100B were assimilated from PDB ID: 1UWO. Almost 2000 complex models were created in HADDOCK by rigid-body minimization. The final 200 models using the lowermost energy outcomes following water refinement were engaged for additional examination. The S100A11–S100B complex model is depicted in Figure 3.

Figure 3.

Figure 3

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Cartoon representing S100A11–S100B complex created with the HADDOCK program. S100A11 is depicted in red and S100B in blue color. Residues near the interaction sites are illustrated in cyan (from the S100A11 side) and yellow (from S100B side) respectively.

In total, two binding sites were identified involving residues S101 and Q102 from S100A11 with S1 from S100B at the first binding site; and N53 and Q54 from S100A11 with H42 from S100B at the second binding site. The structural stereochemistry of the complex was checked through PROCHECK analysis provided online by the European Bioinformatics Institute.86 The Ramachandran plot revealed the presence of 82.1% residues in the maximum favored areas, 13.4% in furthermore permitted areas, 2.8% in allowed regions, and only 1.7% in disallowed regions. The all-inclusive average score of G-factors was found to be 0.19, which is in the expected range (data not included).

Dissociation Constant

In solution, S100A11 and S100B proteins usually occur in homodimeric forms. We first got the HSQC spectrum of 15N S100A11 (Figure 4) in the homodimer form alone.

Figure 4.

Figure 4

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1H–15N HSQC spectra of free 15N S100A11 (red).

We overlapped the HSQC spectrum of the S100A11 homodimer alone (as shown in red color, Figure 5) with the HSQC spectrum of the S100A11 homodimer (15N-labeled) mixed with the S100B homodimer (unlabeled) in a 1:1 ratio (as illustrated in blue color, Figure 5). We found that the two HSQC spectra were exactly the same. This showed that the homodimer of S100A11 does not interact with the homodimer of S100B.

Figure 5.

Figure 5

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1H–15N HSQC spectra overlay of free 15N S100A11 (red) and 15N S100A11 homodimer + S100B homodimer mixture (blue).

Similar results were observed when interaction studies were performed through the isothermal titration calorimetry experiment where titrations were performed by injecting 10 μL aliquots of the S100B homodimer (1 mM, 28 injections) into 0.1 mM of the S100A11 homodimer in the cell (and vice-versa). No binding was observed (data not included). The supposed results were due to the fact that the homodimer of S100A11 did not interact with the homodimer of S100B. However, the monomer of S100A11 will interact with the monomer of S100B to form an S100A11–S100B heterodimer. This conclusion was supported by the following HSQC experiments:

S100A11 (15N-labeled) and S100B (unlabeled) proteins were initially in their homodimeric forms. First, both the proteins were added together (1:1 ratio) followed by denaturation (using 8 M urea to ensure that the monomer was formed for both S100A11 and S100B proteins) and renaturation (removal of 8 M urea by exchanging it with excess deionized water) promoting heterodimer formation. The HSQC spectrum was acquired for this heterodimer. Then this spectrum was overlapped with the HSQC spectrum of the free S100A11 homodimer. The resulting NMR spectra showed a decrease in peak intensities which may be due to the formation of heterodimers (Figure 6). This confirmed the possibility of S100A11–S100B heterodimer formation. So, to get the idea about the dissociation constant, we used the data from the chemical shift perturbations to calculate Kd.

Figure 6.

Figure 6

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1H–15N HSQC spectra overlay of free 15N S100A11 (red) and 15N S100A11–S100B heterodimers (green).

On the basis of the alterations from the chemical shift perturbation, HSQC-NMR titration spectrum analysis can be employed to compute the dissociation constant (Kd).85 The HSQC-NMR spectra of nitrogen-15-labeled S100A11 titrated with unlabeled S100B (and vice-versa) designated the cross-peaks that altered considerably. Residues G29, G58, and Q102 were selected when 15N S100A11 was titrated with unlabeled S100B and residues S1, S18, and I47 were selected with inverse titration for our best model with the succeeding equation

graphic file with name ao-2018-009225_m001.jpg

In the above equation, Δδobs represents the variation detected in the shift among the free and bound-form (1:1 molar ratio). Δδmax represents the maximal shift change at the 1:3 molar ratio, and [P]t and [L]t are the net concentrations of the protein (S100A11) and the ligand (S100B). These equations compute Kd values from the shifts found at diverse concentrations of proteins. At a molar ratio of 1:3 of 15N S100A11 to unlabeled S100B, the mean Kd was ∼2.8 μM. Similarly, inverse calculations (i.e., 15N S100B to unlabeled S100A11) resulted in a mean Kd value of about ∼2.5 μM. Taken together, the average dissociation constant was around ∼2.65 μM (Figure 7). These results indicated that the dissociation constant (Kd) of S100A11 was in the micromolar range.

Figure 7.

Figure 7

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Dissociation constant. Kd calculated by the designated residues detected in 15N S100A11 HSQC titrations with S100B (yellow) and vice-versa (brown). The overall average Kd is about 2.65 μM.

WST-1 Assay

A WST-1-based cell proliferation assay was employed to describe the downstream stimulation of roles transmitted by the RAGE V domain through S100A11. We chose SW-480 cells for our functional assays since they have epithelial-like morphology and are often used to study cancer in vitro. SW-480 cell is a cell line with high expression of RAGE and low expression of the S100A11 protein. Therefore, the role of endogenous S100A11 is not influential and changes in the cell activity can be viewed clearly. The SW-480 cells were treated for 48 h with S100A11 and S100B prior to analysis for viability using the WST-1 assay.

Serum-starved SW-480 cells were matured with S100A11 (100 nM). A 1.728-fold increase was witnessed in the living cell count over the serum-free control (Figure 8, lane 2). This result can be elucidated by the point that S100A11 binds to the RAGE V domain and, thus, induced cell proliferation.87 Similarly, S100B showed a 1.732-fold increase compared to the serum-free control (Figure 8, lane 3) indicating that S100B does bind to RAGE and the interaction of S100B (similar to S100A11) with endogenous RAGE contributes to cell proliferation. However, a 1.44-fold decrease was observed in cells treated with the S100A11–S100B (100 nM) heterodimer protein (Figure 8, lane 4). These results suggest that the S100B protein potentially interferes with the contact between S100A11 and the RAGE V domain, in addition to inhibiting cell proliferation activity.

Figure 8.

Figure 8

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WST-1 assay analysis. The SW-480 cells were treated with 100 nM of S100A11 (dark blue), 100 nM of S100B (light blue), and 100 nM of S100A11–S100B heterodimers (green). The proportional cell counts after subsequent treatment with S100A11 and S100B are depicted as fold inductions with serum-free media alone as the control (red).

S100B Inhibits the S100A11–RAGE V Domain

S100A11 is well-known to exist in a noncovalent homodimeric form having an antiparallel conformation. Molecular interactions between S100A11 and the RAGE V domain have shown that S100A11 binding to the RAGE V domain could eventually trigger an autophosphorylation process leading to numerous signal transduction cascades that regulate cell proliferation and migration.87,88 Here, we used a similar S100A11–RAGE V domain complex model for our studies (Figure 9a).87

Figure 9.

Figure 9

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S100B interfering S100A11–RAGE V domain. (a) The complex model of the S100A11–RAGE V domain constructed via HADDOCK. (b) Superimposition of the complex between S100A11 (red) and the RAGE V domain (green), with the complex amid S100A11 (red) and S100B (blue). (c) The magnified depiction of the clear and significant hindrance to S100A11–RAGE V domain associated with the S100B protein.

Analysis of the S100A11 HSQC spectra with and without unlabeled S100B revealed the S100A11 residues involved in the interaction with S100B. These participating residues near the interaction sites from the S100A11 side were N53, Q54, S101, and Q102. Likewise, S100A11 residues involved in the interaction with the RAGE V domain were N53, Q54, and A90 respectively (Figure 5b).87 Interaction studies related to S100A11 and the RAGE V domain have been performed previously in detail.87 Binding affinity values indicated a stronger interaction between S100A11 and the RAGE V domain when compared to the S100A11–S100B interaction. However, it may be noted that the interaction of S100A11 either with the RAGE V domain or S100B involved a common interaction site (s). Therefore, comparing the S100A11–S100B complex model (obtained through the HADDOCK program) with the S100A11–RAGE V domain complex (constructed in the similar manner87), S100B showed considerable interference. This indicates successful inhibition of the formation of S100A11–RAGE V domain complex (Figure 9b).

Furthermore, through the WST-1 assay it can be understood well that the treatment of exogenous S100A11 and S100B, separately, to SW-480 cells resulted in cell proliferation compared to the control cells. This indicated the interaction of both S100A11 and S100B with the endogenous RAGE V domain giving rise to higher cell counts. However, treatment of the SW-480 cells with the S100A11–S100B heterodimer protein led to a decrease in cell proliferation significantly which indicated that S100B has obstructed the greatly desired interface position of S100A11 and the RAGE V domain needed for higher cell count. In conclusion, an association of S100A11 with S100B has blocked significantly the RAGE signaling causing cell proliferation, and we hypothesize that S100B (or similar antagonist) will disrupt the S100A11–RAGE-mediated signaling significantly in cancerous cells when introduced in higher concentrations.

Conclusions

The biological importance of S100 family proteins associated with RAGE is well-known and S100–RAGE-mediated signaling pathways have been investigated for their role in the progress of many human cancers.89,90 For instance, S100A11 and RAGE signaling have been shown to modulate osteoarthritis pathogenesis.91,92 Additionally, the association of RAGE was found to enhance S100A11 secretion in human squamous cancer cells.28 S100–RAGE-mediated signaling is likely a relevant therapeutic target for the treatment of S100–RAGE-related disorders. In an experimental mouse model, blocking S100–RAGE interactions resulted in the reduction of colonic inflammation and decreased infiltration of inflammatory cells.46,93

Here, we report a study that details the interactions between S100A11 and S100B proteins, proving the interference of S100B in the binding of the S100A11–RAGE V domain in vitro. These data propose that an improvement in the S100B antagonist could greatly impact S100 protein- and RAGE-dependent human diseases. The results from the complex structure analysis confirmed that S100B interferes at the interface region of S100A11 and the RAGE V domain, further highlighting the therapeutic potential of this pathway. In addition, treatment with the S100A11–S100B heterodimer protein in vitro resulted in lower cell numbers in a cancer model.

Overall, our analysis provides prominent structural insights into S100A11–S100B heterodimer complex formation and suggests that an antagonist similar to S100B could be promising for the discovery of new therapies pertaining to S100- and RAGE-mediated diseases.

Materials and Methods

Materials

All the HSQC-NMR experiments were performed utilizing 99% pure isotope-tagged 15N-ammonium chloride (15NH4Cl) and deuterium oxide (D2O). Solutions were formulated using Milli-Q water and sample buffers for the said experiments were purified with a 0.22 μm aseptic device. SW-480 cancer cells were acquired from the American Type Culture Collection (CCL-288).

Expression, Labeling, and Purification

Human S100A1188 and S100B94,95 proteins were expressed and purified as per the protocols mentioned earlier. The purity and identity of the acquired proteins were determined by the sodium dodecyl sulfate (SDS)–polyacrylamide gel electrophoresis (PAGE) gel method and confirmed by electrospray ionization mass spectrometry (ESI-MS) analysis (Supporting Information, Figures S1 and S2).

HSQC-NMR Titration Experiments

All HSQC-NMR experiments were executed inside a Varian 700 MHz spectrometer at 25 °C by utilizing a cryogenic probe. Using an NMR buffer (100 mM NaCl, 5 mM CaCl2, 25 mM Tris/HCl, 1 mM dithiothreitol, 10% D2O, 7.5 pH), an unlabeled S100B protein was supplemented to 15N-labeled-S100A11 at molar ratios of 0:1, 1:1, and 3:1. As these proteins occur in homodimeric forms, they were initially denatured in the presence of 8 M urea before associating as heterodimers.83,96,97 The 8 M urea was completely exchanged with high amounts of water (dialysis will facilitate and ensure the heterodimer formation) and finally replaced with NMR buffer. The converse titration experiments (15N-labeled S100B and unlabeled S100A11) with the similar protocol and molar ratios were carried out as well. The resulting NMR spectra were handled with the VNMRJ 2.3 program and studied further by Sparky 3.198 toward identifying any chemical perturbations, shifts in the cross peaks, or variations in the peak intensities of the protein.

Molecular Docking

The S100A11–S100B complex model was obtained by using the HADDOCK program (version 2.2).99−101 For docking studies, NMR coordinates for S100A11 and S100B were recovered from the Protein Data Bank (PDB ID: 2LUC and PDB ID: 1UWO, respectively).88,94 The residues with detectable chemical shift perturbations or decreased intensity based on HSQC titrations were assimilated for future interaction studies. These residues were included in the Ambiguous Interaction Constraints (AIR) parameters and the residues were assigned as active and passive residues based on the NACCESS program.102 Residues with a comparative accessible surface area >30%, plus side chains and backbone, were considered as active while those <30% were considered as passive residues. A total of 2000 structures were considered for rigid-body docking by using the usual HADDOCK procedure including the optimized potential for liquid simulation parameters.103 Five hundred structures were then considered for semi-flexible refinement, and the next 200 lowest energy structures were examined. All possible structures in clusters were studied and analyzed by the PyMOL program.104

Cell Proliferation Assay

The WST-1 [4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate] cell proliferation assay was executed as per the manufacturer’s (Roche) guidelines.

Acknowledgments

The authors humbly express their gratitude to the associates of the Varian 700 MHz NMR facility at the Instrumentation Center of the Chemistry Department of National Tsing Hua University, and electrospray ionization-MS facility at the Instrumentation Center of National Chiao Tung University, Hsinchu, Taiwan.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b00922.

  • SDS–PAGE and ESI-MS (PDF)

Accession Codes

UniProtKB—P31949 (S10AB_HUMAN), UniProtKB—P04271 (S100B_HUMAN).

This research was sponsored by the Ministry of Science and Technology (MOST) of Taiwan (Grant number MOST 104-2113-M-007-019-MY3) and in part by China Medical University (Grant number CMU104-S-02, Taiwan).

The authors declare no competing financial interest.

Supplementary Material

ao8b00922_si_001.pdf (306.9KB, pdf)

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