Protein Modificomics

From Modifications to Clinical Perspectives

Tanveer Ali Dar, Laishram Rajendrakumar Singh

• Publisher: Academic Press
• Year: 2019
• Print ISBN: 9780128119136
• eBook ISBN: 9780128119501
• Topic: Ciencias biológicas
• Subtopic: Bioquímica

Protein Modificomics: From Modifications to Clinical Perspectives comprehensively deals with all of the most recent aspects of post-translational modification (PTM) of proteins, including discussions on diseases involving PTMs, such as Alzheimer's, Huntington's, X-linked spinal muscular atrophy-2, aneurysmal bone cyst, angelman syndrome and OFC10. The book also discusses the role PTMs play in plant physiology and the production of medicinally important primary and secondary metabolites. The understanding of PTMs in plants helps us enhance the production of these metabolites without greatly altering the genome, providing robust eukaryotic systems for the production and isolation of desired products without considerable downstream and isolation processes. - Provides thorough insights into the post translational modifications (PTMs) of proteins in both the plant and animal kingdom - Presents diagrammatic representations of various protein modification and estimation mechanisms in four-color - Includes coverage of diseases involving post translational modifications

Chapter 1

Posttranslational Modifications of Proteins and Their Role in Biological Processes and Associated Diseases

Irfan-ur-Rauf Tak⁎; Fasil Ali^†; Jehangir Shafi Dar⁎; Aqib Rehman Magray⁎; Bashir A. Ganai⁎; M.Z. Chishti⁎ ^⁎ Centre of Research for Development, University of Kashmir, Srinagar, India
^† Department of PG Studies and Research in Biochemistry, Jnana Kaveri PG Centre, Mangalore University, Chikka Aluvara, India

Abstract

A posttranslational modification (PTM) depicts an imperative means for diversification and regulation of the cellular proteome due to its tremendous scope in various biological processes such as replication, histone modifications, transcription, translation, cell signaling, apoptosis, and cancer, etc. Most PTMs occur in a time- and signal-dependent manner, and determine the overall structure of proteins and also their function in regulating various biological processes. Most PTMs are brought about by small molecular weight functional groups such as phosphate, acyl, acetyl, amide, alkyl, myristoyl, palmitoyl, prenyl, hydroxyl, ubiquitin, and sugars to the amino acid side chains of the protein. Advanced molecular techniques have enumerated more than 200 posttranslational modifications and, in fact, many of them have been discovered recently. Posttranslational modifications can take place at any stage during the maturation of the protein, whereas other modifications usually take place after the process of folding and sorting of proteins and are responsible for their catalytic activity. Study of posttranslational modifications and their mechanism of regulation of various cellular signaling pathways have significant medical implications. Identification, description, and mapping of the posttranslational modifications are very important for discerning their functional implications in a biological context. Therefore, an accurate understanding of protein posttranslational modifications is very important, not only for gaining insight about a multitude of cellular functions and associated diseases, but also regarding drug development for many life-threatening diseases such as neurodegenerative disorders and cancer. The present chapter will therefore attempt to summarize the role of PTMs in various important biological processes and also to provide future insights in this direction.

Keywords

Posttranslational modification; Histone modifications; Ubiquitination; Phosphorylation; Glycans; Myristoylation

1 Introduction

Generally, a posttranslational modification (PTM) is defined as a chemical modification event resulting from either the covalent addition of some functional groups, or proteolytic cleavage to the premature polypeptide chain after translation so that the protein may attain a structurally and functionally mature form. It depicts an imperative means for diversifying and regulating the cellular proteome. Due to the tremendous scope of these chemical alterations in various biological processes like protein regulation, localization, and synergistic relation with other molecules (nucleic acids, lipids, carbohydrates, cofactors), PTMs do play a significant part in functional proteomics. Their significance in proteome functioning is due to their ability to control protein action, location, and synergy with other cell molecules like nucleic acids, proteins, fatty acids, and cofactors. The primary structure of a protein obtained after the process of translation is just the linear sequence of amino acids, which is insufficient to elucidate the protein's biological activity and their regulatory functions. Posttranslational modifications do play a critical role in determining the native functional structure of proteins.

Research in the proteomics field in the last few decades has shown that the complexity of the human proteome is greater than that of the human genome. The human genome is believed to comprise around 20,000–25,000 genes,¹ while over 1 million proteins are known to be present in the human proteome.² This is because a single gene encodes a number of proteins. This enormous diversity of proteins is due to various processes including recombination of genomes, alternative promoter transcription initiation, discrepancies in transcription termination, unusual transcript splicing, and, most importantly, posttranslational modifications.³ The changes that occur to the mRNA at the level of transcription lead to more diversity of transcriptome than the genome, and the innumerable types of PTMs increase proteome diversity many times over compared to transcriptome and genome.

Posttranslational modifications take place in different amino acids side chains, or at peptide linkages, which are frequently mediated by enzymatic activity. Approximately 5% of the proteome is considered to be comprised of enzymes that are identified to carry out more than 200 types of PTMs.⁴ These enzymes include phosphatases, kinases, ligases, transferases, etc. Some of them add various functional groups to the amino acid side chains, while some others remove the functional groups from them. Furthermore, some proteases cleave the peptide bonds of the proteins to remove their specific sequences. These include some enzymes that add or remove the regulatory subunits of the proteins, and hence they play an essential role in regulation. Some proteins even have autocatalytic domains, which have the ability to modify themselves.

A large number of routine cellular processes are regulated by PTMs; for example, phosphorylation of protein, which has been seen as one of the vital control mechanisms that governs the major aspects of cellular life. A majority of the mammalian proteins, which account for nearly 1/3rd of them, are known to contain covalently bound phosphates; the levels of these are said to be controlled by the activities of protein phosphatases and protein kinases, as well as their regulatory subunits. Biological synthesis of the active neuropeptides, which serve as neurotransmitters modulators in both CNS and PNS, is another example of PTM proteolytic processing that involves multiple protease classes. Posttranslational proteolysis also helps in making active enzymes by the conversion of inactive enzyme into its active form, e.g., zymogen (trypsinogen into trypsin).

One of the essential roles of PTM is the macromolecular transport to different cellular spaces by posttranslational glycosylation (e.g., receptor transport by membranes). The intra disulfide bond formed between the two residues of cysteine, which are the backbone for the complex structure and for the purposeful expression of many proteins in enzyme activity, is also well studied by PTM. Many mono-oxygenases (enzymes) which require o₂ for their activity are also linked with PTM; e.g., the amidation of c-terminal peptide transmitters/modulators is catalyzed by peptidyglycine α-amidating monooxygenase and the hydroxylation reactions in hypoxia of the proline residues-inducible factor-1, which is the transcriptional activator catalyzed by prolyl hydroxylases. PTM regulate other enzymes involved in the redox reactions; as a result of this, o₂ availability and redox state alter PTM reactions. Posttranslational modification may take place at any stage during the maturation of the protein. For example, shortly after translation is completed on ribosomes, many proteins are modified to intercede to correct folding/stability of proteins, or direct the nascent protein to specific cellular destinations like membranes, nucleus, lysosomes, etc. Other modifications usually take place after the process of folding and sorting of proteins and are responsible for their catalytic activity.

Some proteins are covalently linked with certain functional groups that are targeted for degradation. Depending upon the nature of modification, posttranslational modification of proteins can be reversible. For example, phosphorylation by protein kinase to the proteins at specific amino acid side chains which are responsible for catalytic activation and inactivation. On the other hand, phosphatases catalyze the hydrolysis of the phosphate group from the protein and, thus, reverse the biological activity. The peptide bond hydrolysis of proteins is a thermodynamically stable reaction and, thus, removes a specific peptide sequence or a regulatory domain permanently. Consequently, analysis of proteins and their PTMs are significant in elucidating the pathological mechanism of diseases like heart disease, cancers, neurodegenerative diseases, arthritis, diabetes, etc. In addition to this, PTMs play a significant part in the functioning of homeostatic proteins, which consequently have a wide range of effects on their capability to interact with other proteins. The characterization of PTMs, although challenging, provides a deep understanding of cellular functions underlying etiological processes. Errors that may occur during posttranslational modifications, either due to hereditary changes or due to environmental effects, may cause a number of human diseases like heart and brain diseases, cancer, diabetes and several other metabolic disorders. Development of specific purification methods are the main challenges that come while going through posttranslationally modified proteins. These challenges are, however, being overcome by using refined proteomic technologies.

For their continued existence, cells should have the ability to interact with other cells and should be able to respond to the external environment. This process of communication between the cells, known as cell signaling, greatly depends upon reversible posttranslational modifications and the quick reprogramming of functions individually. The study of PTMs and their mechanism of regulating various cellular signaling pathways has significant medical implications, in both prevention and cure. In the modern era, understanding the mechanisms of the role key molecules play in signal transduction me...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Contributors
• Preface
• Chapter 1: Posttranslational Modifications of Proteins and Their Role in Biological Processes and Associated Diseases
• Chapter 2: Clinical Perspective of Posttranslational Modifications
• Chapter 3: Phosphorylation and Acetylation of Proteins as Posttranslational Modification: Implications in Human Health and Associated Diseases
• Chapter 4: Protein Modifications and Lifestyle Disorders
• Chapter 5: Ubiquitin Mediated Posttranslational Modification of Proteins Involved in Various Signaling Diseases
• Chapter 6: Role of Glycosylation in Modulating Therapeutic Efficiency of Protein Pharmaceuticals
• Chapter 7: Posttranslational Modification of Heterologous Human Therapeutics in Plant Host Expression Systems
• Chapter 8: Protein Modification in Plants in Response to Abiotic Stress
• Chapter 9: Posttranslational Modifications Associated With Cancer and Their Therapeutic Implications
• Chapter 10: Nonenzymatic Posttranslational Protein Modifications: Mechanism and Associated Disease Pathologies
• Chapter 11: Protein Covalent Modification by Homocysteine: Consequences and Clinical Implications
• Chapter 12: Posttranslational Modifications in Algae: Role in Stress Response and Biopharmaceutical Production
• Chapter 13: Protein Glycosylation: An Important Tool for Diagnosis or Early Detection of Diseases
• Index