Protein-Protein Complexes Through to Interactomics

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Table of Contents

Abstract
Introduction
Combined genomics perspective
Biochemical perspective
Cell biology perspective
Proteomics perspective
Bioinformatics perspective
Conclusions
References

Abstract

This essay assesses the role of protein-protein interactions (PPI) and protein networks in cellular functional pathways. Research demonstrates that protein interactions are vital for the healthy functioning of a cell. It has been demonstrated that protein complexes can activate or inactivate essential pathways in a living cell. This essay examines the various networks of communication within living cells and lays emphasis on the participation of protein complexes in such networks. This is essential in biological research because various protein complexes and networks have been implicated in health and/or unhealthy cell conditions. The essay reviews the aspects of protein-protein complexes through interactomics. It discusses the aspects from a combined genomic, biochemical, proteomics, cell biological and bioinformatics perspective.

Introduction

The study of the protein interaction pathways helps in understanding the roles of various protein complexes in cellular pathways. It has been established that proteins interact and form biologically important complexes with other biomolecules in the living cells (Uversky, Gillespie & Fink 2000). The other biomolecules include DNA, RNA (nucleic acids), fatty acids and hormones. The complexes formed have been confirmed to be involved in the growth and development and regulation of cellular activities, for example, metabolism and signal transduction (Kiemer & Cesareni 2007).

Interactomics is geared towards genome-wide studies to decipher the whole genomes of species (Jones & Thornton1996). One of the most characterized interactomes is that of Saccharomyces cerevisiae. Its protein interactions have been fairly characterized because of it its simple genome (Furga 2002). The Caenorhabditis elegans and Drosophila melanogaster have also been studied to some extent to decipher their interactomes (Ho et al 2002). For example, the full genome sequences of Caenorhabditis elegans have helped study the genes that might be interacting with crucial proteins for cell regulation. Various methods have been developed to study protein-protein interactions in living cells. These methods include two-hybrid screening, X-ray chromatography, tandem affinity chromatography and optical fluorescence microscopy.

Interactomics research has been characterized by criticisms. The procedures involved in getting interactome data have been found to be prone to errors. Results from interactomics experiments have been found to have a high probability of being incorrect. This is due to the fact that interactomics studies the relationship between proteins and other biomolecules in the cell. For example, the impact of interaction between DNA and proteins on gene expression. The proteins and the other biomolecules could be undergoing mutations, thus giving wrong results. That notwithstanding, interactomics is an interesting area of study in modern biological research. This has been due to the fact that it gives crucial information on cellular networks responsible for healthy and unhealthy conditions.

Combined genomics perspective

Genome of a species is the total number of genes within that species. Thus, genomics is the study of all genes of organisms. Genomics concentrates on finding and understanding DNA sequences. DNA is an essential molecule in all organisms because it is regarded as being the blueprint of life. In the study of genes and their functions, researchers have tried to decipher, in depth, the processes of transcription, splicing and translation. The end-product of translation is protein. Proteins are involved in many activities in the body (Bartel 2004). They are involved in growth and development, they act as hormones and they are involved in signal transduction pathways in the cell. Genomics and interactomics have been found to be linked primarily because the two fields of study involve the study of cellular biomolecules (Rubin et al 2005). Whereas interactomics is concerned with protein interaction networks, genomics is concerned with the genes within cells. Genes are either activated or inactivated within cells. When they are activated, they are expressed, and they give their gene products. Some of the activating complexes have been confirmed to be protein complexes, which signal gene expression pathways. The knowledge on DNA interactions with proteins has brought new ideas of how cellular pathways are interlinked. Many human genetic disorders have been shown to involve interaction of genomes and interactomes (Hartwell et al 1999). The networks formed through the interactions are crucial in the development and progression of disease conditions. It requires knowledge on both genomes and interactomics to comprehend the mechanisms of complex genetic disorders. Some of these complex genetic disorders are epilepsy and Alzheimer’s disease. This has been made possible by the development and utilisation of high-throughput technologies and computational resources (Ren et al 2000). High-throughput technologies give huge amounts of data while computational resources store and help in biological data analysis.

Understanding the protein networks involved in the cellular activation of genes is crucial because scientists can further understand the pathways involved in cell signal transduction pathways. For example, the cellular components that activate genes so that they are expressed in a living cell. Constitutively expressed genes are expressed continuously, thus their gene products are in high production within and outside a cell. It has been suggested that the gene activation pathways encompass protein complexes that signal the gene transcription activators to be active continuously while inhibiting the transcription inhibitors. This has become so critical in understanding the mechanisms of development and progression of cancers and tumours. For example, the onset of breast cancer has been linked with activation of breast cancer genes in the breasts. Thus, the knowledge on protein-protein interactions and genomics is essential in the study of disease states of human beings. This is possible because many technologies have been developed to assess gene activation patterns in the cell, and assay for the activating factors (Bandyopadhyay & Mehler 2008).

Biochemical perspective

Interactomics have been studied by attempting to decipher the patterns of interaction, and the characteristics of the protein complexes formed. Protein complexes are made up of biomolecules which are biochemically linked. Understanding the biochemical properties of the participating biomolecules in a protein complex is essential to deciphering the biological implication of the complex. The interactomics data have been widely applied in pharmacology and cell biology, among other fields of biology (Brownlee 2001).

X-ray crystallography is one of the widely applied techniques in learning the structure and properties of interacting biomolecules. Together with NMR, they give 3-D structure of molecules. This 3-D structure of the biomolecules can be used to predict the biological function of protein complexes. Electron microscopy has also been used together with X-ray crystallography to give better 3-D structures of protein complexes (Gygi et al 2000). Protein complexes have also been studied by use of sequence data from sequencing projects. This has been possible because sequences of proteins and other molecules like the DNA are visualised through genome sequencing. With the sequence data, it is possible to predict structural features of biomolecules. The two-hybrid system has also been used to predict the structure of molecules (Kortemme & Baker 2002). Other methods include microarrays and phage display techniques. It has been possible to study most structures of molecules because of the use of the computer. When novel structures are found in research laboratories, they are deposited in computer databases where the scientific community can access it. Scientists compare their findings in the laboratories with what is already deposited in the large databases.

It has been demonstrated that many protein interactions can be studied by identifying common structural features in biomolecules. These features could be phylogenetically conserved, or they could have developed as a result of evolutionary pressures leading to convergence. The structures of the protein complexes determine the chemical bonding in the structure. Research has demonstrated that protein structures could be linked strongly, weakly or moderately strong. What determine the intensity of chemical bonding are the chemical components of the participating biomolecules. The chemicals further determine the types of bonds formed when chemical linkages are formed. In proteins, motifs determine the type of chemical bonding formed between protein linkages. Protein motifs are the functional units of proteins. They are the protein parts that determine the functions of proteins. In enzymes, the functional units are the binding sites which link with specific substrate to catalyse a chemical reaction.

Cell biology perspective

Cell biology is the branch of biology that is concerned with the study of cells. Cells are the physiological functional units in living organisms. They have cell organelles which perform different functions in the cell. Protein complexes are formed during the protein synthesis. The complexes formed depend on the signals directing the assembly of proteins. Different polypeptide chains are joined to make a protein. Proteins exist in four structures. Protein synthesis in the rough endoplasmic reticulum and subsequent transport to various destinations is carried out by complexes of molecules in the cell. The molecules are in interactomes of specific locations and functions. Thus, research has underscored the link between cellular functions and networks of biomolecules.

Cell biology has been involved in the study of how cells contribute to disease states of biological systems. Research has studied cells extensively to understand their role in cancer development and progression. It has been demonstrated that the normal growth of cells is inhibited in cancerous cells. Research on interactomics has suggested involvement of complex protein networks in such inhibitions. Interactomes have been cited to be involved in conversions of oncogenes into proto-oncogenes. In normal cells, proto-oncogenes accelerate cell growth and proliferation. On the other hand, tumor suppressor genes inhibit cell growth and proliferation.

The study of cell biology encompasses understanding the various functions of the cell. The key functions of the cell are performed by networks of biomolecules. The process requires ATP expenditure. Normal physiological functions of the body require binding of cells to a surface. Cellular adhesion is accomplished by a group of protein molecules namely: selectins, integrins and cadherins (Pardal, Clarke & Morrison 2003). Cellular adhesion is essential in cellular signal transduction pathways that activate or inactivate cellular activities. If cells are not able to express the right adhesion molecules, then diseases occur. For example, during the spread of cancer cells there is altered cell adhesion and migration integrity of cells.

Cellular metabolism is a collection of enzyme characterised activities that take place in the cell. The metabolic processes are essential for digestion and transport of substances, among other functions. Catabolism involves chemical breakdown while anabolism involves build-up of biomolecules. These two processes of metabolism are co-ordinated by networks of cellular machinery crucial for initiating and maintaining the process.

Proteomics perspective

Proteomics is concerned with the study of proteins, their features and physiological roles. Proteins are essential physiological units of cells. It is an important area of study because researchers can manipulate genes of organisms to understand their functional genomics. Scientists perform complex genomic-based experiments to understand the roles of the genes expressed in a cell by studying the properties and functions of proteins produced (Rual 2005). It has been demonstrated that messenger RNA does not correspond to the protein synthesised by a cell. This was a great puzzle in the past before it was found that the mRNA transcript is subjected to many chemical modifications. Most of the modifications occur after translation of the mRNA. The first modification is phosphorylation which is the introduction of a phosphate to specific parts of a polypeptide chain. Serine and threonine are the amino acids onto which phosphate is mostly introduced. Phosphorylation is a crucial biochemical event that is required for cell signalling. Tyrosine kinases are essential in marking molecules for phosphorylation. Therefore, phosphorylation is a network-based chemical modification process that is essential for the functioning of cellular components.

Ubiquitination is another cellular biochemical event that is crucial in understanding regulation of essential protein networks. The protein pathways are regulated by many enzymes like ligases and kinases. Thus, the pathway can be characterised by gaining knowledge on the types of enzymes involved in the regulation process.

The Enzyme-Linked Immunosorbent Assay (ELISA) is a specific test used to assess the amounts of samples with proteins. Mass spectrometry is also used to measure the amount of proteins in samples. Other methods have been developed to study the types of post-translational modifications on proteins. Some involve the use of antibodies which bind to the modified proteins. If the expected modified proteins are in a sample, then the test antibodies bind to the proteins and a signal to show the binding is given. These methods are intended to be very specific. The commonly used method is two-dimensional electrophoresis (Santoni, Molloy & Rabilloud 2000).

It has been demonstrated many proteins function when they have interacted with other proteins (protein complexes). Proteomics has been concerned with identifying the types of proteins involved in such interactions. The identification of the proteins in protein complexes is essential because it gives hints on the proteins involved in cell signalling networks. Proteomic studies have used two-hybrid analysis, protein microarrays and mass spectrometry to identify partners in protein-protein interactions (Lockhart & Winzeler 2000). Other laboratory bases techniques involve the use of phage system and computations. The knowledge of proteomics and interactomics has been utilised to develop new drugs. This has been achieved through the use of computer software. First, genome information is used to predict the proteins that might be involved in a disease. After this, computer software is used to target the predicted proteins with potential therapeutic agents. The most crucial part in drug design is the identification of 3-D structure. The 3-D structure provides information on the active site of the proteins. In short, drug discovery projects involve the use of potential drugs to inactivate proteins in affected tissues. Genetic studies are giving a new promise of developing personalised drugs for individuals. This will result in improved clinical outcomes because there will not be any guess work on the best drug for an individual.

Bioinformatics perspective

Bioinformatics is a computer-based field of study that aims at generating biological information by utilizing computer tools. Bioinformatics is concerned with the generation, storage, retrieval, organisation and analysis of biological data. Biological data analysis is done by the use of computer software (Saeys, Inza & Larrañaga 2007).

Protein complexes are predicted to gain knowledge on interaction partners using computational biology tools. When such complexes are identified and characterised, it is easy to decipher processes at the molecular level that are implicated in not only normal physiological states but also in abnormal physiological states. The knowledge has been utilised to understand the involvement protein complexes in disease states. High-throughput technologies have provided huge amounts of data on protein interactions. However, such data has been found to have errors in interactions. Thus, it is prudent for biological scientists to validate methods of assaying for protein-protein interactions. Bioinformatics encompasses both static and dynamic approaches to model biological systems. However, both approaches follow the basic activities in bioinformatics. These are alignment of sequences (both DNA and protein), analysis of the sequences and creation of 3-D structures of proteins.

The approaches then study how the sequences interact in biological systems. This is so crucial in interactomics. Microarray data (RNA, DNA and protein microarrays) are used to compare sequences. Dynamic approaches are concerned with the study of structures in biological systems. These are structures are those of proteins, DNA, RNA and peptides. This is a crucial step in interactomics because the results from such studies are used to understand the interaction dynamics of protein dynamics. It has been demonstrated that most interactions involve proteins and proteins, proteins and ligands, and proteins and peptides. However, to understand the molecular interactions bioinformatics has been concerned with the study of the movement of biochemical bonds in biomolecules. This is accomplished through the use of computational algorithms. The approaches involve understanding cellular processes that are crucial in cell functions. These processes are the signal transduction pathways, transcription and reaction patterns in the cells (Oinn et al 2004).

Bioinformatics has several branches. For example, comparative genomics is concerned with the study of structure and functions of genes across species. Scientists are able to identify processes that are common across species. In addition, through the use of intergenomic maps, scientists have been able to study evolutionary mechanisms across species. They have been able to understand the genes that have been under genetic pressure to mutate as well as those that are evolutionary conserved. Cellular events are controlled by regulatory complexes in the cell. Bioinformatics also endeavours to understand and identify regulatory sequences in gene expression.

Bioinformatics is essential in the study and analysis of protein expression in biological samples. Bioinformatics uses data obtained from protein microarrays and mass spectrometry to match them against known data that are stored in databases. The matching of the microarray and mass spectrometry data is done by use of statistical tools that are very specific to peptides within a biological protein sample (Stevens, Robinson & Goble 2003). Therefore, bioinformatics play a crucial role in the study of protein-protein interactions. It is essential in understanding the cellular protein networks involved in regulation of cellular physiological events.

Conclusions

Proteins interact with each other to form protein complexes. Apart from protein-protein interactions (PPI), proteins interact with other components like the DNA, RNA, lipids and ligands to form protein complexes. Such interactions are crucial for normal and abnormal functions of living cells. The biochemical bonds involved in protein complexes are covalent linkages that may be weak, strong or moderately strong. The strength of the bonds formed greatly determines the chemical reactions in which the complexes can participate. From a genomic point of view, protein complexes are involved in regulation of cellular genomes. They activate or inactivate genes, leading to normal or abnormal physiological conditions in the cell. From a biochemical perspective, interactions among protein components in the cell occur as a result of chemical bonding. The interactions are determined by the chemical properties of the participating protein molecules. In relation to proteomics, protein interactions are essential in the expression of proteins and activities of proteins in the cell. The interactions are key components in protein synthesis and their transport to various locations. From a cell biology perspective, protein complexes and interactomics are essential in regulation of cellular activities. From a bioinformatics perspective, protein interactions and networks are studied through the use of computer resources and software to understand the complex mechanisms involved in cell regulation and physiological pathways. The study of interactomics is crucial in modern biology in understanding the role of cellular networks in healthy and unhealthy conditions.

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