Nanotechnologies in Glycoproteomics
© Zhao et al.; licensee BioMed Central Ltd. 2014
Received: 29 November 2013
Accepted: 17 March 2014
Published: 13 May 2014
Protein glycosylation, as an important post-translational modification, is implicated in a number of ailments. Applying proteomic approaches, including mass spectrometry (MS) analyses that have played a significant role in biomarker detection and early diagnosis of diseases, to the study of glycoproteins or glycopeptides will facilitate a deeper understanding of many physiological functions and biological pathways involved in cancer, inflammatory and degenerative diseases. The abundance of glycopeptides and their ionization potential are relatively lower compared to those of non-glycopeptides; therefore, sample enrichment is necessary for glycopeptides prior to MS analysis. The application of nanotechnology in the past decade has been rapidly penetrating into many diverse scientific research disciplines. Particularly in what we now refer to as the “glycoproteomics area”, nanotechnologies have enabled enhanced sensitivity and specificity of glycopeptide detection in complex biological fluids, which are critical for disease diagnosis and monitoring. In this review, we highlight some recent studies that combine the capabilities of specific nanotechnologies with the comprehensive features of glycoproteomics. In particular, we focus on the ways in which nanotechnology has facilitated the detection of glycopeptides in complex biological samples and enhanced their characterization by MS, in terms of intensity and resolution. These studies reveal an increasingly important role for nanotechnology in helping to overcome certain technical challenges in biomarker discovery, in general, and glycoproteomics research, in particular.
Protein glycosylation is one of the most common post-translational modifications (PTMs) in living cells [1, 2]. Glycoproteins play a vital role in biological processes including cell adhesion, receptor activation, and signal transduction [3–5]. As such, altered or erroneous glycosylation is often associated with inflammatory diseases, neurodegenerative disorders, and even certain cancers [6, 7]. For example, several investigators have observed that the abnormal expression of different glycosylated proteins were implicated in disease and that changes in the level of glycoprotein could be used as hallmarks for disease diagnosis, including the carbohydrate antigen CA-19-9 for colon cancer , the prostate-specific antigen (PSA) for prostate cancer , α-fetoprotein for liver cancer , and β-human chorionic gonadotropin for germ cell tumors . Furthermore, many accessible, membrane-bound or extracellular proteins are glycosylated and could be exploited for therapeutic intent, such as the Her2 receptor for breast cancer therapy .
Glycoproteins are not as amenable to isolation and identification due confounding factors such as complex glycan structures, glycan isomers, and amino acid residues attached to the oligosaccharide chains. The most commonly employed technique for the analysis of protein glycosylation (glycosylation site identification, glycan structure determination, site occupancy, and glycan isoform distribution) is MS, albeit with still a few existing technical challenges . In this review, we will highlight some of the platforms that have been developed for the enrichment of glycopeptides from complex samples, and introduce emerging combination platforms that couple the sensitivity and accuracy of MS to the exquisite selectivity of nano-platforms.
Different nano-platforms used to enrich glycopeptides
A nanomaterial is a natural, incidental or manufactured material containing particles in an unbound, aggregate or agglomerate state, where one or more external dimensions is in the size range 1–100 nanometers. Due to their smaller size, nanomaterials possess incredibly larger surface areas than bulky materials. This feature provides more activated sites for glycopeptide enrichment and unique optical properties, in the context of rapid and sensitive detection. Perhaps the most attractive characteristic of nanomaterials is the degree to which their size, shape and morphology can be precisely controlled to enhance the optical, electronic, or magnetic capabilities typically desired in certain applications. Several nano-platforms exist for the isolation of glycopeptides in complex samples with improved sensitivity and specificity, and we discuss them in more details in the following Subsections.
Nanoparticles for glycopeptide enrichment
Nanoparticles are arguably the most widely used nanomaterial to assemble chips for biomolecule enrichment because: 1) nanoparticles can be synthesized with various size distributions, and morphologies; 2) nanoparticles can be modified and diversified by numerous reagents for specific uses; and 3) they exhibit unique optical and electrochemical features. When attempting to enrich glycopeptides in complex samples, researchers often adopt core-shell structured nanoparticles with a magnetic core within a thin layer of compatible material. The magnetic core, which provides a strong magnetic force, would be simply attracted by magnets and the outer layer would be easily modified by various organic or inorganic reagents to recognize the biomarker of interest.
Using a version of the above approach, Zhou et al. fabricated aminophenyl boronic acid-functionalized magnetic nanoparticles and used them to selectively capture glycopeptides and glycoproteins from mixtures containing non-glycomoleculars . Other groups have also applied versions of surface-modified nanoparticles for glycoprotein selection. For example, 3-aminopropyltriethoxysilane (APTES) is frequently used as a surface-modifying reagent for silica nanoparticles, whereby the amino group imparts a positive charge. Zhang Y. and coworkers designed a one-step salinization reaction to assemble APTES onto the nanoparticle surface in order to capture aldehyde groups on oxidized glycopeptides. These nanoparticles greatly reduced the coupling time from 12–16 hours to just 4 hours without sacrificing enrichment efficiency, compared to traditional solid-phase extraction methods based on hydrazide resins . Zhang L. et al. developed a novel composite material with a core-satellite structure. These are gold nanoparticles, functionalized with boronic acid, and then anchored on the surface of the silica-coated magnetic core. Using this strategy, the investigators were able to recover 85.9% of glycopeptides and 71.6% of glycoproteins after enrichment. The composite nanoparticles had an adsorption capacity of more than 79 mg of glycoproteins per gram of the material. The investigators used these new composite nanoparticles to enrich glycosylated proteins from human colorectal cancer tissues for subsequent identification of N-glycosylation sites. They were able to map 194 unique glycosylation sites, of which 165 sites (85.1%) were newly identified, to 155 different glycoproteins .
Polysaccharides can also be used as a surface-modifying component for glycopeptide enrichment. Xiong et al. reported a layer-by-layer approach to synthesize magnetic nanoparticles (MNPs) that are coated with multilayered polysaccharide shells, and then used these hydrophilic materials for selective enrichment of glycopeptides from biological samples. These investigators identified 605 unique N-glycosylation sites in 616 distinct glycopeptides, corresponding to 350 glycosylated proteins in 20 μg mouse liver protein sample. Their results indicated that exploiting specific sugar-sugar interactions shows promise as a design strategy for characterizing protein glycosylation .
Rather than using boronic acid as a surface-modifying reagent for nanoparticles, Tran et al. developed a new kind of gold nanoparticles, functionalized with ultra-small hydrazide groups, with a core diameter of 1.2 nm. The assembly process involves an oxidation step and covalent coupling, whereby the carbohydrate moiety of the glycoproteins are oxidized into aldehydes by periodate and the oxidized glycoproteins are covalently coupled to hydrazide resin. No glycoproteins are removed by washing. They successfully utilized these nanoparticles to isolate 90% of the glycopeptides from complex biological samples. The nanoparticle stability in biological solution, unique solubility, and large capacity for peptide capturing provide great application potential in glycoproteomics studies .
Isolating glycopeptides via their lectin moiety is another common approach, and commercialized solutions are now available in the market. Tsutsumi and colleagues conjugated gold nanoparticles (GNPs) with monosaccharide-modified peptides as optical probes for lectin detection. The aggregation of the glycopeptide-modified GNPs with concanavalin A (ConA) causes an absorption shift from 534 nm to 620 nm, an apparent color change that can be detected by the naked eye .
Ligand-modified nanoparticles have been proven to be an excellent platform for glycopeptide enrichment, but ligand-free nanoparticles are emerging as good candidates for glycoproteins or glycopeptides isolation. A research group in Fudan University developed ligand-free silver nanoparticles coated with magnetic nanoarchitecture for selective enrichment of glycopeptides by taking advantage of the reversible interaction of glycans with silver nanoparticles. The investigators could easily and quickly (only 1 min incubation time) extract glycopeptides at a low molar ratio of glycopeptides: non-glycopeptides (1:100) using these silver-nanoparticle magnetic beads. Moreover, they mapped 127 unique glycopeptides mapped to 51 different glycoproteins from a very small sample volume (only 1 μL rat serum) .
Particle-based materials are the most widely adopted for isolating and separating glycosylated peptides due to their nano dimensionality, tightly controlled size, and unique optical and electrochemical properties. They will likely continue to play a prominent role in glyco-proteomics for biomarker detection and early diagnosis of diseases.
Mesoporous materials for glycopeptide enrichment
Several classes of porous materials exist and group according to size. The International Union of Pure and Applied Chemistry (IUPAC) clarifies , microporous materials and macroporous materials as having pore diameters less than 2 nm and greater than 50 nm, respectively; mesoporous materials place in the middle. Developed since the 1970’s, mesoporous silica materials are, at present, widely used in drug delivery, imaging, biosensors, for example, owing to their regular pore arrangement, simple preparatory methods, and low cost. Under the influence of strong capillary forces, biomolecules entering the mesoporous pores encounter more activation sites for binding, resulting in higher separation efficiency. Many glycoproteomics studies have been conducted using mesoporous materials for glycopeptide isolation and separation.
Oxidized mesoporous carbon is another very useful material in glycoproteomics research because of its extraordinary hydrophilicity. Hence, oligosaccharides on N-linked glycans interact with the carbon functional groups, enabling glycopeptide separation prior to profiling by MS. Using this approach, Qin et al. enriched N-linked glycans using oxidized and ordered mesoporous carbon materials of CMK-3 before matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS. Twenty four N-linked glycans derived from standard glycoproteins could be detected with high signal-to-noise (S/N) ratios and peak intensities. Thirty-two N-linked glycans were profiled in complex samples, five (4 core-fucosylated glycans) of which exhibited distinct patterns in liver cancer compared to healthy samples. Their results support the notion that precisely-sized mesoporous carbon materials could play a prominent role in clinical glycoproteomics .
With such broad applicability and adaptability, we expect the use of mesoporous materials to continue leaving an impact on the glycoproteomics landscape. The large specific surface area, surface modification potential, size exclusion toward large molecular weight biomolecules, and support strong capillary force in nano scale are all characteristics that lend well to their wide-spread use.
Other nano platforms for glycopeptide enrichment
Carbon nanotubes (CNTs) are allotropes of carbon exhibiting a cylindrical nanostructure. These cylindrical carbon molecules have unusual properties that could be, and is currently, exploited by the electronics industry, optics industry, and other fields of materials science and technology. Zhang X. and colleagues constructed a novel lectin-based electrochemical biosensor of functionalized, multi-walled CNTs to capture glycans from living cells . They fabricated the biosensor by adsorbing poly(diallyldimethylammonium chloride) (PDDA)-functionalized CNTs (PDCNTs) onto a glassy carbon electrode (GCE), followed by glutathione (GSH)-protected gold nanoparticles (AuNPs) adsorption. The resulting material becomes an effective platform for lectin immobilization, with high stability and bioactivity. The investigators also synthesized a thiol-derivatized carbohydrate (thiomannosyl dimer) to construct (CNT/thionine/Au–S–mannose) biocomposites, which used CNTs as carriers to load enormous amounts of thionine (to generate an electrochemical signal) and AuNPs (to anchor the thiomannosyl dimer).
The two applications for functionalized CNTs, whether as a biosensing platform and biocomposite, allow enhanced glycan signal detection. The former (electrochemical biosensor) has demonstrated good analytical performance – high sensitivity, selectivity and rapid response – for the analysis of mannose in human lung cancer cells. This approach could be adapted for other indications by broadening the selection moiety (e.g., lectins) for biosensor development.
Conclusion and perspective
Investigators have long recognized the significance of protein glycosylation in physiological processes and disease, as evidenced by the number of related publications that continue to accumulate. Furthermore, glycosylated proteins are increasing identified as biomarkers for early disease detection of diseases via proteomics methods. Although recent advances in mass spectrometry have made large-scale identification of proteins feasible, it is still very challenging to analyze protein glycosylation in complex samples owing to the fact that glycopeptides often constitute a minor portion of the total peptide mixture, whose signal intensities are often lower compared to non-glycosylated peptides and are suppressed in the presence of non-glycopeptides. Nanotechnology has undoubtedly contributed to the realization of glycoprotein/glycopeptide enrichment methods, particularly from enrichment from complex samples in preparation for MS characterization. The use of nanomaterials with various morphologies and characteristics (nanoparticles, mesoporous materials, nanosheets, nanotubes, etc.) has enabled enhanced sensitivity and specificity of glycopeptides isolation.
Challenges do remain in detecting post-translationally modified proteins/peptides, especially circulating glycopeptides. Characterizing glycosylated peptides is also difficult due to unique electrochemical properties, optical properties, and energy brand structure. By applying nano-scaled materials to tunable platforms, scientists have greatly enhanced the capabilities of traditional MS-based techniques, by increasing mass resolution, mass range, mass intensities, to name a few. We believe this significant progress blazes a trail for future efforts (and accomplishments) in the combined areas of nano-engineering, MS and glycoproteomics.
HZ, YL and YH participated the drafting of the manuscript. All of the authors read and approved the final manuscript.
We like to acknowledge DOD innovator award (DoD W81XWH-09-1-0212), NIH U54CA151668, Bill & Melinda Gates Foundation and DoD W81XWH-11-2-0168.
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