10 ways to look at the human proteome
Antibody-based immunoassays are widely used in exploratory preclinical and pharmaceutical research as tools for discovering new druggable protein targets. Read about the 10 ways to explore and map the human proteome and how it helps researchers and clinicians on their discovery journeys.
A key and ultimate aspect of biomedical research lies in translating the discoveries into clinical use, meaning the development of new diagnostic tools to prevent or treat human diseases.
To this end, the selection and validation of novel molecular targets have become of paramount importance. Since the vast majority of the targets of approved drugs are proteins, one way of identifying new potential drug targets is to analyze the human proteome at multiple levels: protein type, distribution, classification, and structural data in both healthy and cancerous tissue.
Antibody-based immunoassays are widely used in exploratory preclinical and pharmaceutical research as tools for discovering new biomarkers and druggable protein targets.
The Swedish Human Protein Atlas project has mapped all the human proteins in tissue, organs, and organelle using Triple A Polyclonal antibodies from Atlas Antibodies. Read about the 10 ways to explore the human proteome and how this helps researchers and clinicians on their discovery journeys.
Approved drugs target proteins and their function
Identifying new targets is a crucial part of any drug development program.
Today, almost all pharmaceutical drugs act by targeting proteins in the human body and affect their activity. Specifically, over 95% of the currently known drug targets are proteins (Santos 2017). Antagonists are drugs that inactivate the protein target, while drugs that activate the protein target are called agonists.
Target proteins mainly belong to four protein families, i.e., enzymes, transporters, ion channels, and receptors. The most frequent protein targeted (and for which successful drugs have been developed) include proteases, protein kinases, G protein-coupled receptors (GPCRs), CD markers, and nuclear hormone receptors (Imming 2006, Zheng 2006).
The protein targeted by a drug should potentially be linked to a disease process with less significant involvement in other important processes to limit potential side-effects, have an expression pattern allowing for drug efficacy by showing tissue-specific expression and have structural and functional properties allowing for drug specificity.
Hence, a precise human proteome map at multiple levels helps clinicians better detect proteins and molecular processes involved in health and disease and diagnose human conditions such as cancers, neurodegenerative, and other neurological disorders.
Figure 1. Cancer proteomes on the Human Protein Atlas website. Interactive chapters of 17 human cancer types exploring the mRNA and protein expression data, including genes associated with prognosis.
A protein snapshot is what we need
To help map out the morphological landscape of the human proteome, clinicians and researchers focused on immuno-histopathology, the study of tissues and cells.
Immunohistochemistry (IHC) and fluorescence immunocytochemistry (ICC-IF) bridge three disciplines: immunology, histology, and chemistry. The fundamental concept is the demonstration of antigens within a cell or tissue sections by means of specific antibodies.
Once focused mainly on the classification of neoplasms (in combination with morphology), IHC and ICC-IF have also been used to investigate the entire human proteome in real-time, leading to a better understanding of diseases pathogenesis with applications in diagnosis, prognosis, and therapeutic decisions.
Figure 2. The tissue cell-type proteomes on the Human Protein Atlas website. Interactive chapters: by selecting a tissue, you will access the tissue information, the cell types analyzed and which genes had predicted specificity in each tissue, and examples of protein IHC staining.
The Human Protein Atlas
The Human Protein Atlas (HPA) is a Swedish-based program born in 2003 aiming at mapping all the human proteins in cells, tissues, and organs using an integration of various omics technologies, including antibody-based imaging, mass spectrometry-based proteomics, transcriptomics, and systems biology.
All the data is open access to allow scientists in academia and industry to freely explore the human proteome.
While the knowledge of the number of proteins is valuable, it is also helpful to consider the families to which these proteins belong ideally under physiological conditions.
To this end, the HPA uses antibody-based strategies to analyze the spatio-temporal aspects of the human proteome. The antibody-based approach provides spatial information at high resolution (not available with other analytical tools such as mass spectrometry). Similarly, other advanced techniques such as X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, used to determine the three-dimensional structures of proteins, require pulling the proteins out of their natural cellular environment.
The antibody-based approach of the human proteome has a clear advantage, namely the identification of human proteins at a single-cell resolution in their original environment with ‘real-time’ localization in tissue, cells, and subcellular levels.
With over 3.6 M visits annually, the HPA is one of the world’s most visited biological open-access databases. The updated version, HPA v.21, released in November 2021, contains new information, including revised summary pages for all human protein-coding genes, a revised dictionary for educational purposes, and a new methods summary with details on how the data in each section has been generated, analyzed, and visualized.
The Human Protein Atlas is a valuable resource that helps you discover properties of proteins that ultimately may be important in determining their suitability for pharmaceutical modulation.
Figure 3. The subcellular and organelle proteomes on the Human Protein Atlas website. A collection of interactive pages providing different perspectives of the distribution of proteins in human cells. Overviews, compilations, and analyses of the data generated within the subcellular section: the multilocalizing, organelle, and cell cycle-dependent proteome.
10 ways to look at the human proteome
The Human Protein Atlas consists of ten separate but interconnected sections, each focusing on a particular aspect of the genome-wide analysis of the human proteome:
The Tissue section shows the distribution of the proteins across all major tissues and organs in the human body.
The Brain section explores the distribution of proteins in various mammalian brain regions.
The Single Cell Type section shows the expression of protein-coding genes in single human cell types based on scRNA-seq.
The Tissue Cell Type section shows the expression of protein-coding genes in human cell types based on bulk RNAseq data.
The Pathology section shows the impact of protein levels on the survival of patients with cancer.
The Immune Cell section shows the expression of protein-coding genes in immune cell types.
The Blood Protein section describes proteins detected in blood and proteins secreted by human tissues.
The Subcellular section shows the subcellular localization of proteins in single cells.
The Cell Line section shows the expression of protein-coding genes in human cell lines.
The Metabolic section explores the expression of protein-coding genes in the context of the human metabolic network.
Figure 4. The 10 ways to look at the human proteome. The Human Protein Atlas consists of ten separate but interconnected sections, each focusing on a particular aspect of the genome-wide analysis of the human proteome.
The Human Protein Atlas Dictionary
The purpose of the dictionary is to facilitate the interpretation and use of the image-based data available in the Human Protein Atlas but also to serve as a tool for training and understanding histology, pathology, and cell biology. The dictionary contains three main parts: normal tissue histology, pathology, and cell structure.
The aim of this section is to educate readers about the histology of normal and cancer tissues, which provides important and basic information for our understanding of biology and medicine. The dictionary covering cell structure is built around antibody-based stainings of proteins in cell lines using immunofluorescence and confocal microscopy.
How do Atlas Antibodies support the Human Protein Atlas?
As part of creating the human protein expression map, researchers from the Human Protein Atlas project developed highly-specific polyclonal antibodies targeting all protein-coding human genes.
The over 20,000 epitope-directed polyclonal antibodies employed in the Human Protein Atlas are manufactured and commercialized by Atlas Antibodies as Triple A Polyclonals™ (Atlas Antibodies Advanced Polyclonals).
All Triple A Polyclonals are carefully designed and manufactured to achieve the very highest level of specificity, reproducibility, and versatility. They are validated in IHC, WB, ICC-IF on all major tissues and organs in the human body as well as the 20 most common cancer types. For each antibody, over 500 staining images of all major human tissue, organs, and cancer types are freely available on the HPA website.
The full HPA publication list is available here.
Imming P, Sinning C, Meyer A. Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Erratum in: Nat Rev Drug Discov. 2007 Feb;6(2):126.
Santos R, Ursu O, Gaulton A, Bento AP, Donadi RS, Bologa CG, Karlsson A, Al-Lazikani B, Hersey A, Oprea TI, Overington JP. A comprehensive map of molecular drug targets. Nat Rev Drug Discov. 2017 Jan;16(1):19-34.
Zheng CJ, Han LY, Yap CW, Ji ZL, Cao ZW, Chen YZ. Therapeutic targets: progress of their exploration and investigation of their characteristics. Pharmacol Rev. 2006 Jun;58(2):259-79.