Synthesis and Degradation

This section focuses on molecular mechanisms underlying the regulation of protein concentration and active forms of proteins both inside and outside cells and highlights dis- eases/pathologies that can result in dysregulation of proteins. Just as the knowledge/understanding of RNA and DNA and other fundamental components of cells and tissues have evolved, so have those of the proteins that make up cells, the extracellular environment, and fluids of living organisms.

The complexity of the interactions of proteins has become apparent and the importance of networks of proteins (death pathways, blood coagulation, complement), interacting proteases (the 'protease web'), extracellular matrix, intracellular scaffolds, and membrane, organelle, and factor interactions with intracellular and extracellular proteins are now clearly realized.

Many of the structures involved in the synthesis of proteins have been solved (including the ribosome, translation factors) and there has been considerable progress clarifying the mechanisms that control initiation, elongation, and termination in eukaryotic cells (see Components, Initiation, Elongation, Termination, and Regulation). Similarly the components of the mitochondrial protein biosynthetic machinery and mechanisms of transcription and translation have been elucidated (see The Protein Biosynthetic Machinery of Mitochondria).

Many proteins are synthesized as inactive or latent proteins (proproteins) and have to be activated by enzymes such as proprotein convertases and kallikreins (see Regulated Proteolysis of Signaling Molecules: The Proprotein Convertases; Kallikrein). Biosynthesis of secretory proteins that takes place in the endoplasmic reticulum (ER) involves multiple factors (signalases, chaperones, iso-merases) to form a mature correctly folded protein (see Biogenesis of Secretory Proteins). Factors are in place for quality control in the ER to recognize and shuttle incorrectly folded proteins into the ER-associated degradation pathway (see Endoplasmic Reticulum-Associated Degradation and Protein Quality Control).

It was once believed one protease could degrade many proteins in a relatively unregulated manner (somewhat like trypsin in the intestinal tract). It is now known that there are multiple proteases in all cells and fluids that are highly regulated. There are -600 genes for proteases in the human genome and if there were no regulation there would be widespread necrosis, cell death, and destruction.

It is clear that proteolytic systems are highly regulated by localization, activation/inhibition, synthesis of latent proenzymes, interactions with multiple components such as cofactors, carbohydrates, lipids, membranes, organelles, and the pH of the environment.

The complement of all proteases and their substrates is known as 'the degradome' and high-throughput methods have recently been developed to study the network of protease and substrate interactions (see Mass Spectrometry-based Methodologies for Studying Proteolytic Networks and the Degradome).

Proteolytic systems exist both intracellularly and extracellularly as well as at cell membranes. The mammalian intestinal system serves as a good example of coordinated digestion of food proteins that involves many different types of extracellular proteases (see Digestive Proteases: Roles in the Human Alimentary Tract).

Blood coagulation represents another extracellular system that is critical to host defense and hemostasis and involves cells (e.g., platelets), a host of plasma proteins (most of which are proteases) and protease inhibitors, which are highly controlled to form and degrade blood clots appropriately (see Overview of Blood Coagulation and the Pathophysiology of Blood Coagulation Disorders).

The complement system involves highly regulated proteolytic enzymes critical to our immune systems that remove targeted pathogens (see Molecular Mechanisms Underlying the Actions of the Complement System).

The proteasome is key to intracellular proteolytic systems and works in coordination with ubiquitin-tagged proteins for protein quality control and several signaling systems (see Ubiquitin, Ubiquitin-Like Proteins, and Proteasome-Mediated Degradation). In addition, the intracellular lysosomal system containing multiple hydrolases (e.g., proteases, glycosidases) that interact with cellular and extracellular components to degrade and maintain protein/amino acid homeostasis (see Role of Lysosomes in Intracellular Degradation).

Dysregulation of all of these systems is associated with disease, and there are specific articles on lysosomal storage diseases (see Lysosomal Diseases) and the proteases involved in the progression of cancer (see Cancer - Proteases in the Progression and Metastasis).

Individual proteases are discussed in many articles and some that are highlighted are matrix metalloproteinases (see Matrix Metalloproteinases), calpain (see The Calpain Proteolytic System), ADAMS and ADAMTS (see ADAMTS Proteases: Mediators of Physiological and Pathogenic Extracellular Proteolysis; ADAMs Regulate Cell-Cell Interactions by Controlling the Function of the EGF-Receptor, TNFa and Notch), membrane-anchored serine proteases (see Extracellular: Plasma Membrane Proteases - Serine Proteases), meprins (see Metalloproteases Meprin a and Meprin ß in Health and Disease), kallikreins (see Kallikrein), and aspartic proteases (see Aspartic Proteases of Alzheimer's Disease: ß- and y-Secretases; Cathepsin E: An Aspartic Protease with Diverse Functions and Biomedical Implications).

Protease inhibitors are also critical to the regulation of protein degradation and disease. Endogenous polypeptide protease inhibitors exist for many of the proteolytic systems (e.g., apoptosis, blood coagulation; Naturally-Occurring Polypeptide Inhibitors: Cystatins/Stefins, Inhibitors of Apoptosis (IAPs), Serpins, and Tissue Inhibitors of Metalloproteinases (TIMPs)).

Alpha-1-antitrypsin deficiency is an example of how important endogenous protein inhibitors are for preventing disease, as this deficiency leads to liver damage and emphysema (see Alpha-1-Antitrypsin Deficiency: A Misfolded Secretory Glycoprotein Damages the Liver by Proteotoxicity and Its Reduced Secretion Predisposes to Emphysematous Lung Disease Because of Protease-Inhibitor Imbalance). Examples of synthetic protease inhibitors used to control disease process are blood pressure inhibitors (ACE inhibitors; Blood Pressure, Proteases and Inhibitors) and HIV-proteasе inhibitors that have been designed to manage AIDS (see Inhibitors of HIV Protease).

In summary, the purpose of part I of the Encyclopedia is to describe the chemical principles and the molecular components/organization of the cell and its environment in sufficient detail to allow a clearer understanding of how these components are then assembled, function, and are regulated at a higher level - the themes of the next three parts of the Encyclopedia.