Proteomics is the large-scale study of proteins, particularly their structures and functions. Proteins are vital parts of living organisms, as they are the main components of the physiological metabolic pathways of cells. The term proteomics was first coined in 1997 to make an analogy with genomics, the study of the genome. The word proteome is a portmanteau of protein and genome, and was coined by Marc Wilkins in 1994 while working on the concept as a PhD student.
The proteome is the entire set of proteins, produced or modified by an organism or system. This varies with time and distinct requirements, or stresses, that a cell or organism undergoes. Proteomics is an interdisciplinary domain formed on the basis of the research and development of the Human Genome Project; it is also emerging scientific research and exploration of proteomes from the overall level of intracellular protein composition, structure, and its own unique activity patterns. It is an important component of functional genomics.
While proteomics generally refers to the large-scale experimental analysis of proteins, it is often specifically used for protein purification and mass spectrometry.
- 1 Complexity of the problem
- 2 Limitations of genomics and proteomics studies
- 3 Methods of studying proteins
- 4 Establishing protein–protein interactions
- 5 Practical applications of proteomics
- 6 Structural proteomics
- 7 Expression proteomics
- 8 Interaction proteomics
- 9 Proteomics and system biology
- 10 Current proteomic technologies
- 11 Bioinformatics for proteomics (proteome informatics)
- 12 Emerging trends in proteomics
- 13 See also
- 14 References
- 15 Bibliography
- 16 External links
Complexity of the problem
After genomics and transcriptomics, proteomics is the next step in the study of biological systems. It is more complicated than genomics because an organism's genome is more or less constant, whereas the proteome differs from cell to cell and from time to time. Distinct genes are expressed in different cell types, which means that even the basic set of proteins that are produced in a cell needs to be identified.
In the past this phenomenon was done by RNA analysis, but it was found not to correlate with protein content. It is now known that mRNA is not always translated into protein, and the amount of protein produced for a given amount of mRNA depends on the gene it is transcribed from and on the current physiological state of the cell. Proteomics confirms the presence of the protein and provides a direct measure of the quantity present.
Not only does the translation from mRNA cause differences, but many proteins are also subjected to a wide variety of chemical modifications after translation. Many of these post-translational modifications are critical to the protein's function.
One such modification is phosphorylation, which happens to many enzymes and structural proteins in the process of cell signaling. The addition of a phosphate to particular amino acids—most commonly serine and threonine mediated by serine/threonine kinases, or more rarely tyrosine mediated by tyrosine kinases—causes a protein to become a target for binding or interacting with a distinct set of other proteins that recognize the phosphorylated domain.
Because protein phosphorylation is one of the most-studied protein modifications, many "proteomic" efforts are geared to determining the set of phosphorylated proteins in a particular cell or tissue-type under particular circumstances. This alerts the scientist to the signaling pathways that may be active in that instance.
Ubiquitin is a small protein that can be affixed to certain protein substrates by enzymes called E3 ubiquitin ligases. Determining which proteins are poly-ubiquitinated helps understand how protein pathways are regulated. This is, therefore, an additional legitimate "proteomic" study. Similarly, once a researcher determines which substrates are ubiquitinated by each ligase, determining the set of ligases expressed in a particular cell type is helpful.
In addition to phosphorylation and ubiquitination, proteins can be subjected to (among others) methylation, acetylation, glycosylation, oxidation and nitrosylation. Some proteins undergo all these modifications, often in time-dependent combinations. This illustrates the potential complexity of studying protein structure and function.
Distinct proteins are made under distinct settings
Even studying a particular cell type, that cell may make different sets of proteins at different times, or under different conditions. Furthermore, as mentioned, any one protein can undergo a wide range of post-translational modifications.
Therefore a "proteomics" study can become complex, even if the topic of the study is restricted. In more ambitious settings, such as when a biomarker for a tumor is sought – when the proteomics scientist is obliged to study blood serum samples from multiple cancer patients.
Limitations of genomics and proteomics studies
Proteomics gives a different level of understanding than genomics for many reasons:
- the level of transcription of a gene gives only a rough estimate of its level of translation into a protein. An mRNA produced in abundance may be degraded rapidly or translated inefficiently, resulting in a small amount of protein.
- as mentioned above many proteins experience post-translational modifications that profoundly affect their activities; for example some proteins are not active until they become phosphorylated. Methods such as phosphoproteomics and glycoproteomics are used to study post-translational modifications.
- many transcripts give rise to more than one protein, through alternative splicing or alternative post-translational modifications.
- many proteins form complexes with other proteins or RNA molecules, and only function in the presence of these other molecules.
- protein degradation rate plays an important role in protein content.
Reproducibility. Proteomics experiments conducted in one laboratory are not easily reproduced in another. For instance, Peng et al. have identified 1504 yeast proteins in a proteomics experiment of which only 858 were found in a similar previous study. Further, the previous study identified 607 proteins that were not found by Peng et al. This translates to a reproducibility of 57% (Peng vs. Washburn) to 59% (Washburn vs. Peng).
Methods of studying proteins
Protein detection with immunoassays
The enzyme-linked immunosorbent assay (ELISA) has been used for decades to detect and quantitatively measure proteins in samples.
The use of mass spectrometric immunoassay is the gold standard for both discovery and quantitative proteomics. Randall Nelson pioneered the use of immunoassays with mass spectrometry in 1995.
SISCAPA. Stable Isotope Standard Capture with Anti-Peptide Antibodies, is a term introduced by Leigh Anderson
Identifying proteins that are post-translationally modified
One way a particular protein can be studied is to develop an antibody specific to that modification. For example, there are antibodies that only recognize certain proteins when they are tyrosine-phosphorylated, known as phospho-specific antibodies. Also, there are antibodies specific to other modifications. These can be used to determine the set of proteins that have undergone the modification of interest.
A more common way to determine post-translational modification of interest is to subject a complex mixture of proteins to electrophoresis in two-dimensions, which simply means that the proteins are electrophoresed first in one direction, and then in another, which allows small differences in a protein to be visualized by separating a modified protein from its unmodified form. This methodology is known as "two-dimensional gel electrophoresis".
Recently, another approach has been developed called PROTOMAP, which combines SDS-PAGE with shotgun proteomics to enable detection of changes in gel-migration, such as those caused by proteolysis or post translational modification.
Determining the existence of proteins in complex mixtures
For proteomic study, more recent techniques such as matrix-assisted laser desorption/ionization (MALDI) have been employed for rapid determination of proteins in particular mixtures and increasingly electrospray ionization (ESI).
More recently, thermal protease resistance was exploited in a novel proteomic assay called Fast parallel proteolysis (FASTpp), which enabled detection of specific proteins in E. coli lysate and might be used in the future to detect proteomic perturbations in cancer or mechanistic effects of point mutations.
Establishing protein–protein interactions
Most proteins function in collaboration with other proteins, and one goal of proteomics is to identify which proteins interact. This is especially useful in determining potential partners in cell signaling cascades.
Several methods are available to probe protein–protein interactions. The traditional method is yeast two-hybrid analysis. New methods include surface plasmon resonance (SPR), protein microarrays, immunoaffinity chromatography followed by mass spectrometry, dual polarisation interferometry, Microscale Thermophoresis and experimental methods such as phage display and computational methods.
Practical applications of proteomics
One major development to come from the study of human genes and proteins has been the identification of potential new drugs for the treatment of disease. This relies on genome and proteome information to identify proteins associated with a disease, which computer software can then use as targets for new drugs. For example, if a certain protein is implicated in a disease, its 3D structure provides the information to design drugs to interfere with the action of the protein. A molecule that fits the active site of an enzyme, but cannot be released by the enzyme, inactivates the enzyme. This is the basis of new drug-discovery tools, which aim to find new drugs to inactivate proteins involved in disease. As genetic differences among individuals are found, researchers expect to use these techniques to develop personalized drugs that are more effective for the individual.
The National Institutes of Health has defined a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”
Understanding the proteome, the structure and function of each protein and the complexities of protein–protein interactions is critical for developing the most effective diagnostic techniques and disease treatments in the future. For example, proteomics is highly useful in identification of candidate biomarkers (proteins in body fluids that are of value for diagnosis), identification of the bacterial antigens that are targeted by the immune response, and identification of possible immunohistochemistry markers of infectious or neoplastic diseases.
An interesting use of proteomics is using specific protein biomarkers to diagnose disease. A number of techniques allow to test for proteins produced during a particular disease, which helps to diagnose the disease quickly. Techniques include western blot, immunohistochemical staining, enzyme linked immunosorbent assay (ELISA) or mass spectrometry. Secretomics, a subfield of proteomics that studies secreted proteins and secretion pathways using proteomic approaches, has recently emerged as an important tool for the discovery of biomarkers of disease.
In what is now commonly referred to as proteogenomics, proteomic technologies such as mass spectrometry are used for improving gene annotations. Parallel analysis of the genome and the proteome facilitates discovery of post-translational modifications and proteolytic events, especially when comparing multiple species (comparative proteogenomics).
Current research methodologies
Fluorescence two-dimensional differential gel electrophoresis (2-D DIGE) can be used to quantify variation in the 2-D DIGE process and establish statistically valid thresholds for assigning quantitative changes between samples.
Comparative proteomic analysis can reveal the role of proteins in complex biological systems, including reproduction. For example, treatment with the insecticide triazophos causes an increase in the content of brown planthopper (Nilaparvata lugens (Stål)) male accessory gland proteins (Acps) that can be transferred to females via mating, causing an increase in fecundity (i.e. birth rate) of females. To identify changes in the types of accessory gland proteins (Acps) and reproductive proteins that mated female planthoppers received from male planthoppers, researchers conducted a comparative proteomic analysis of mated N. lugens females. The results indicated that these proteins participate in the reproductive process of N. lugens adult females and males.
There are many approaches to characterizing the human proteome, which is estimated to contain between 20,000 and 25,000 non-redundant proteins. The number of unique protein species will likely increase by between 50,000 and 500,000 due to RNA splicing and proteolysis events, and when post-translational modification are also considered, the total number of unique human proteins is estimated to range in the low millions.
In addition, the first promising attempts to decipher the proteome of animal tumors have recently been reported.
Structural proteomics includes the analysis of protein structures at large-scale. It compares protein structures and helps identify functions of newly discovered genes. The structural analysis also helps to understand that where drugs bind to proteins and also show where proteins interact with each other. This understanding is achieved using different technologies such as X-ray crystallography and NMR spectroscopy.
Expression proteomics includes the analysis of protein expression at larger scale. It helps identify main proteins in a particular sample, and those proteins differentially expressed in related samples—such as diseased vs. healthy tissue. If a protein is found only in a diseased sample then it can be a useful drug target or diagnostic marker. Proteins with same or similar expression profiles may also be functionally related. There are technologies such as 2D-PAGE and mass spectrometry that are used in expression proteomics.
Interaction proteomics is the analysis of protein interactions at larger scale. The characterization of protein-protein interactions are useful to determine the protein functions and it also explains the way proteins assemble in bigger complexes. Technologies such as affinity purification, mass spectrometry, and the yeast two-hybrid system are particularly useful in interaction proteomics.
Proteome analysis techniques are not simple and straightforward as those used in transcriptomics. The benefit of proteomics, however, is that it deals with the real functional molecules of the cells. It is known that strong gene expression results in an abundant mRNA but it does not necessarily mean that the corresponding protein is also abundant. In proteomics things are not so simple as one gene does not always produce the same protein. The genes usually consist of a series of sub structures, which are called exons. These sub structures can be joined in a variety of ways, which helps to give momentum to a whole series of very similar but different proteins. Further increasing complications, once proteins are made, they are ornamented with different other chemicals. These chemicals can be phosphate, sugars or fats. The effect of the decorations is severe on the function of protein; for example phosphate normally behaves as an on-off switch and sugars usually tell the proteins where to go and attach in the cell. Therefore, it was comparatively very simple and easy to sequence the human genome as there are only 46 molecules and they are made up of 4 building blocks or letters (A, C, G, T) whereas proteins have 20 building blocks, each of which can be customized or ornamented after the protein is built. Hence, proteomics have to deal with ca. 30,000 genes that can be arranged to give some 800,000 proteins that can be modified and decorated with over 300 different chemicals. Additionally, proteomics also describe the nature of proteins, where they are being produced in a particular cell type and at a specific time, the way they are modified in the cell, the location where they are modified and also what they are in contact with. Finally, the most difficult thing is to determine the function of the protein.
Proteomics and system biology
Proteomics has recently come into the act as a promising force to transform biology and medicine. It is becoming increasingly apparent that changes in mRNA expression correlate poorly with protein expression changes. Proteins change enormously in patterns of expressions across developmental and physiological responses. Proteins also face changes on the act of environmental perturbations. Proteins are the actual effectors driving cell behavior. The field of proteomics strives to characterize protein structure and function, protein-protein, protein-nucleic acid, protein-lipid, and enzyme-substrate interactions, protein processing and folding, protein activation, cellular and sub-cellular localization, protein turnover and synthesis rates, and even promoter usage. Integrating proteomic data with information such as gene, mRNA and metabolic profiles helps in better understanding of how the system works.
Current proteomic technologies
Proteomics has steadily gained momentum over the past decade with the evolution of several approaches. Few of these are new and others build on traditional methods. Mass spectrometry-based methods and micro arrays are the most common technologies for large-scale study of proteins.
Mass spectrometry and protein profiling
There are two mass spectrometry-based methods currently used for protein profiling. The more established and widespread method uses high resolution, two-dimensional electrophoresis to separate proteins from different samples in parallel, followed by selection and staining of differentially expressed proteins to be identified by mass spectrometry. Despite the advances in 2DE and its maturity, it has its limits as well. The central concern is the inability to resolve all the proteins within a sample, given their dramatic range in expression level and differing properties.
The second quantitative approach uses stable isotope tags to differentially label proteins from two different complex mixtures. Here, the proteins within a complex mixture are labeled first isotopically, and then digested to yield labeled peptides. The labeled mixtures are then combined, the peptides separated by multidimensional liquid chromatography and analyzed by tandem mass spectrometry. Isotope coded affinity tag (ICAT) reagents are the widely used isotope tags. In this method, the cysteine residues of proteins get covalently attached to the ICAT reagent, thereby reducing the complexity of the mixtures omitting the non-cysteine residues.
Quantitative proteomics using stable isotopic tagging is an increasingly useful tool in modern development. Firstly, chemical reactions have been used to introduce tags into specific sites or proteins for the purpose of probing specific protein functionalities. The isolation of phosphorylated peptides has been achieved using isotopic labeling and selective chemistries to capture the fraction of protein among the complex mixture. Secondly, the ICAT technology was used to differentiate between partially purified or purified macromolecular complexes such as large RNA polymerase II pre-initiation complex and the proteins complexed with yeast transcription factor. Thirdly, ICAT labeling was recently combined with chromatin isolation to identify and quantify chromatin-associated proteins. Finally ICAT reagents are useful for proteomic profiling of cellular organelles and specific cellular fractions.
Another quantitative approach is the Accurate Mass and Time (AMT) tag approach developed by Richard D. Smith and coworkers at Pacific Northwest National Laboratory. In this approach, increased throughput and sensitivity is achieved by avoiding the needed for tandem mass spectrometry, and making use of precisely determined separation time information and highly accurate mass determinations for peptide and protein identifications.
Balancing the use of mass spectrometers in proteomics and in medicine is the use of protein micro arrays. The aim behind protein micro arrays is to print thousands of protein detecting features for the interrogation of biological samples. Antibody arrays are an example in which a host of different antibodies are arrayed to detect their respective antigens from a sample of human blood. Another approach is the arraying of multiple protein types for the study of properties like protein-DNA, protein-protein and protein-ligand interactions. Ideally, the functional proteomic arrays would contain the entire complement of the proteins of a given organism. The first version of such arrays consisted of 5000 purified proteins from yeast deposited onto glass microscopic slides. Despite the success of first chip, it was a greater challenge for protein arrays to be implemented. Proteins are inherently much more difficult to work with than DNA. They have a broad dynamic range, are less stable than DNA and their structure is difficult to preserve on glass slides, though they are essential for most assays. The global ICAT technology has striking advantages over protein chip technologies.
Reverse-phased protein microarrays
This is a promising and newer microarray application for the diagnosis, study and treatment of complex diseases such as cancer. The technology merges laser capture microdissection (LCM) with micro array technology, to produce reverse phase protein microarrays. In this type of microarrays, the whole collection of protein themselves are immobilized with the intent of capturing various stages of disease within an individual patient. When used with LCM, reverse phase arrays can monitor the fluctuating state of proteome among different cell population within a small area of human tissue. This is useful for profiling the status of cellular signaling molecules, among a cross section of tissue that includes both normal and cancerous cells. This approach is useful in monitoring the status of key factors in normal prostate epithelium and invasive prostate cancer tissues. LCM then dissects these tissue and protein lysates were arrayed onto nitrocellulose slides, which were probed with specific antibodies. This method can track all kinds of molecular events and can compare diseased and healthy tissues within the same patient enabling the development of treatment strategies and diagnosis. The ability to acquire proteomics snapshots of neighboring cell populations, using reverse phase microarrays in conjunction with LCM has a number of applications beyond the study of tumors. The approach can provide insights into normal physiology and pathology of all the tissues and is invaluable for characterizing developmental processes and anomalies.
Bioinformatics for proteomics (proteome informatics)
There is a large amount of proteomics data being collected with the help of high throughput technologies such as mass spectrometry and microarray. It would often take weeks or months to analyze the data and perform comparisons by hand. For this reason, biologists and chemists are collaborating with computer scientists and mathematicians to create programs and pipeline to computationally analyze the protein data. Using bioinformatics techniques, researchers are capable of faster analysis and data storage. A good place to find lists of current programs and databases is on the ExPASy bioinformatics resource portal <http://www.expasy.org/proteomics>. The applications of bioinformatics-based proteomics includes medicine, disease diagnosis, biomarker identification, and many more.
Mass spectrometry and microarray produce peptide fragmentation information but do not give identification of specific proteins present in the original sample. Due to the lack of specific protein identification, past researchers were forced to decipher the peptide fragments themselves. However, there are currently programs available for protein identification. These programs take the peptide sequences output from mass spectrometry and microarray and return information about matching or similar proteins. This is done through algorithms implemented by the program which perform alignments with proteins from known databases such as UniProt <http://www.uniprot.org/> and PROSITE <http://prosite.expasy.org/> to predict what proteins are in the sample with a degree of certainty.Template:Methods Mol Biol. 2007;367:87-119. Three such programs are MASCOT <http://www.matrixscience.com/>, PeptideMass <http://web.expasy.org/peptide_mass/>, and SPIRE (https://www.proteinspire.org/SPIRE/).
The biomolecular structure forms the 3D configuration of the protein. Understanding the protein's structure aids in identification of the protein's interactions and function. It used to be that the 3D structure of proteins could only be determined using X-ray crystallography and NMR spectroscopy. Now, through bioinformatics, there are computer programs that can predict and model the structure of proteins. These programs use the chemical properties of amino acids and structural properties of known proteins to predict the 3D model of sample proteins. This also allows scientists to take a look at protein interactions on a larger scale. In addition, biomedical engineers are developing methods to factor in the flexibility of protein structures to make comparisons and predictions.
Unfortunately, most programs available for protein analysis are not written for proteins that have undergone post-translational modifications. Some programs will accept post-translational modifications to aid in protein identification but then ignore the modification during further protein analysis. It is important to account for these modifications since they can affect the protein's structure. In turn, computational analysis of post-translational modifications has gained the attention of the scientific community. The current post-translational modification programs are only predictive. Chemists, biologists and computer scientists are working together to create and introduce new pipelines that allow for analysis of post-translational modifications that have been experimentally identified for their effect on the protein's structure and function.
Computational methods in studying protein biomarkers
One example of the use of bioinformatics and the use of computational methods is the study of protein biomarkers. Computational predictive models have shown that extensive and diverse feto-maternal protein trafficking occurs during pregnancy and can be readily detected non-invasively in maternal whole blood. This computational approach circumvented a major limitation, the abundance of maternal proteins interfering with the detection of fetal proteins, to fetal proteomic analysis of maternal blood. Computational models can use fetal gene transcripts previously identified in maternal whole blood to create a comprehensive proteomic network of the term neonate. Such work shows that the fetal proteins detected in pregnant woman’s blood originate from a diverse group of tissues and organs from the developing fetus. The proteomic networks contain many biomarkers that are proxies for development and illustrate the potential clinical application of this technology as a way to monitor normal and abnormal fetal development.
An information theoretic framework has also been introduced for biomarker discovery, integrating biofluid and tissue information. This new approach takes advantage of functional synergy between certain biofluids and tissues with the potential for clinically significant findings not possible if tissues and biofluids were considered individually. By conceptualizing tissue-biofluid as information channels, significant biofluid proxies can be identified and then used for guided development of clinical diagnostics. Candidate biomarkers are then predicted based on information transfer criteria across the tissue-biofluid channels. Significant biofluid-tissue relationships can be used to prioritize clinical validation of biomarkers.
Emerging trends in proteomics
A number of emerging concepts have the potential to improve current features of proteomics. Obtaining absolute quantification of proteins and monitoring post-translational modifications are the two tasks that impacts the understanding of protein function in healthy and diseased cells. Advances in quantitative proteomics would clearly enable more in-depth analysis of cellular systems. For many cellular events, the protein concentrations do not change; rather, their function is modulated by post-transitional modifications (PTM). Methods of monitoring PTM are an underdeveloped area in proteomics. Selecting a particular subset of protein for analysis substantially reduces protein complexity, making it advantageous for diagnostic purposes where blood is the starting material. Another important aspect of proteomics, yet not addressed, is that proteomics methods should focus on studying proteins in the context of the environment. The increasing use of chemical cross linkers, introduced into living cells to fix protein-protein, protein-DNA and other interactions, may ameliorate this problem partially. The challenge is to identify suitable methods of preserving relevant interactions. Another goal for studying protein is to develop more sophisticated methods to image proteins and other molecules in living cells and real time.
Human plasma proteome
Characterizing the human plasma proteome has become a major goal in the proteomics arena. The plasma proteome is without doubt the most complex proteome in the human body. It contains immunoglobulin, cytokines, protein hormones, and secreted proteins indicative of infection on top of resident, hemostatic proteins. It also contains tissue leakage proteins due to the blood circulation through different tissues in the body. The blood thus contains information on the physiological state of all tissues and, combined with its accessibility, makes the blood proteome invaluable for medical purposes. Even with the recent advancements in proteomics, characterizing the proteome of blood plasma is a daunting challenge.
Temporal and spatial dynamics further complicate the study of human plasma proteome. The turnover of some proteins is quite faster than others and the protein content of an artery may substantially vary from that of a vein. All these differences make even the simplest proteomic task of cataloging the proteome seem out of reach. To tackle this problem, priorities needs to be established. Capturing the most meaningful subset of proteins among the entire proteome to generate a diagnostic tool is one such priority. Secondly, since cancer is associated with enhanced glycosylation of proteins, methods that focus on this part of proteins will also be useful. Again: multiparameter analysis best reveals a pathological state. As these technologies improve, the disease profiles should be continually related to respective gene expression changes.
- Activity based proteomics
- Bottom-up proteomics
- Functional genomics
- Heat stabilization
- Human proteome project
- List of biological databases
- List of omics topics in biology
- Proteomic chemistry
- Shotgun proteomics
- Top-down proteomics
- Systems biology
- Yeast two-hybrid system
- Human Protein Atlas
- Cardiac Organellar Protein Atlas Knowledgebase (COPaKB)
- Human Protein Reference Database
- GPM Database (GPMDB)
- Multi-Omics Profiling Expression Database (MOPED)
- National Center for Biotechnology Information (NCBI)
- Protein Data Bank (PDB)
- Protein Information Resource (PIR)
- Proteomics Identifications Database (PRIDE)
- Proteopedia The collaborative, 3D encyclopedia of proteins and other molecules
- European Bioinformatics Institute
- Netherlands Proteomics Centre (NPC)
- Proteomics Research Resource for Integrative Biology (NIH)[dead link]
- Global map of proteomics labs
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|last10=in Authors list (help);
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