All things you need to know about the Role of Globular Proteins

Introduction

Globular proteins are a type of protein that can dissolve in water and have a tight, spherical form. These proteins are involved in a wide range of biological processes, such as enzyme activation, molecule recognition, intracellular signaling, and maintaining structure. This in-depth study will look at the different roles that globular proteins play in different biological processes, the things that affect their activity, and how important they are for keeping cellular balance stable.

1. Enzymatic Catalysis

1.1 Basic Principles of Enzyme Catalysis

Enzymes are spherical proteins that speed up chemical processes by lowering the activation energy needed for the reaction to take place. They do this by giving the process another way to go that has a smaller energy barrier. Enzymes are very specific and good at what they do. They often have a high level of preference for their source and can speed up reactions.

The unique three-dimensional shape of an enzyme’s active site, which binds the substrate and speeds up the process, is what gives it its uniqueness. The active site is usually a small pocket or groove on the surface of a protein. It is made up of a few amino acid residues that help link substrates and speed up the reaction. Most of the time, interactions between enzymes and substrates are caused by non-covalent forces, such as hydrogen bonds, hydrophobic forces, and ionic forces.

Most of the time, there are two key steps in enzyme catalysis: the formation of an enzyme-substrate complex and the change of the substrate into a product or products. The interactions between the active site of the enzyme and the substrate strengthen the enzyme-substrate complex. This creates a transition state that makes the process go more quickly. Once the reaction is done, the product(s) are released and the enzyme goes back to its original state, ready to start another reaction.

1.2 Enzyme Classes and Functions

Based on what kind of process they speed up, enzymes are put into six main groups. Each class is further split into subclasses and sub-subclasses based on the chemical process involved. There are six main types of enzymes, which are:

• Oxidoreductases: Oxidoreductases are enzymes that speed up oxidation-reduction processes, in which one molecule loses electrons and another gets them. Some examples are peroxidases, which break down peroxides, and dehydrogenases, which speed up the movement of electrons between molecules.

• Transferases: Transferases are proteins that help a useful group, like a methyl or phosphate group, move from one molecule to another. Kinases, which move phosphate groups from one protein to another, and transaminases, which move amino groups between amino acids and keto acids, are two examples.

• Hydrolases: By putting a water molecule across a bond, hydrolases speed up the breakdown of different bonds. Complex molecules like proteins, nucleic acids, and lipids are broken down with the help of these enzymes. Proteases, which break peptide bonds in proteins, and nucleases, which break phosphodiester bonds in nucleic acids, are two kinds of enzymes that do this.

• Lyases: Lyases are enzymes that break bonds in ways other than hydrolysis or oxidation. This usually results in a new double bond or ring structure. Some examples are aldolases, which break carbon-carbon bonds in aldol substrates, and decarboxylases, which take a carboxyl group off of an organic acid.

• Isomerases: Isomerases move atoms around inside a molecule, changing it from one isomer to another. Racemases, which change L-amino acids into D-amino acids, and isomerases, which change cis-fatty acids into trans-fatty acids, are two examples of these kinds of enzymes.

• Ligases: Ligases help make new links between molecules. This process is often linked to the breaking of a high-energy phosphate bond in ATP. DNA ligase, which joins DNA strands during replication and repair, and carboxylases, which help add a carboxyl group to a molecule, are two examples.

2. Molecular Recognition and Binding

Globular proteins are involved in many chemical interactions and bindings in biological systems, such as interactions between proteins, proteins and nucleic acids, and proteins and ligands. Many biological processes, such as signaling, gene production, and defense reaction, depend on these relationships.

2.1 Antibody-Antigen Interactions

Antibodies, which are also called immunoglobulins, are round proteins made by the immune system in reaction to antigens, which are foreign substances. Antibodies identify and link to their target antigens, which neutralizes them or tells immune cells to destroy them. The antigen-binding site of an antibody is made up of its varying regions, which are what allow it to bind to its antigen. Because these areas vary a lot, antibodies can recognize a wide range of antigens with great sensitivity and affinity.

2.2 Hormone-Receptor Interactions

Hormones are chemicals that send signals and control a number of bodily functions, such as growth, metabolism, and reproduction.Hormones do what they do by attaching to specific receptors, which are often on the cell surface or inside the target cell. When a hormone binds to its receptor, it sets off a chain of events inside the cell that lead to a reaction from the cell. Globular proteins like insulin and growth hormone are examples of peptide hormones that work with cell surface receptors to control how glucose is used and how cells grow.

2.3 Protein-Nucleic Acid Interactions

Interactions between proteins and nucleic acids are important for many biological processes, such as the replication, transcription, and translation of DNA. Globular proteins like DNA polymerases, RNA polymerases, and ribosomal proteins identify and bind to specific nucleic acid patterns or structures. This helps make new DNA or RNA molecules or decode the genetic information in mRNA. The precision of these interactions comes from the fact that the protein and nucleic acid units have similar forms and electrostatic properties.

2.4 Protein-Protein Interactions

Protein-protein interactions are important for the formation and function of multi-subunit protein complexes as well as the control of many biological processes. Non-covalent interactions between globular proteins include hydrogen bonds, hydrophobic interactions, and ionic interactions. The precision and strength of protein-protein interactions rely on how the surfaces of the involved proteins have similar forms, charges, and levels of hydrophobicity. Enzyme-substrate complexes, receptor-ligand complexes, and the formation of cytoskeletal strands are all examples of protein-protein interactions.

3. Signal Transduction and Intracellular Signaling

Signal transduction is the process by which external signals, like hormones or chemicals, are turned into internal signals that make a cell do something. Globular proteins work as sensors, signal transmitters, and effector molecules, which are all very important parts of signal transmission paths.

3.1 G-Protein Coupled Receptors (GPCRs)

GPCRs are a big family of spherical membrane-bound proteins that turn signals from outside the cell into signals inside the cell by activating G proteins inside the cell. When a ligand, like a hormone or neurotransmitter, links to a GPCR, it causes the receptor to change its shape, which makes it possible for the receptor to turn on a nearby G protein. G proteins are made up of three different parts called subunits: alpha, beta, and gamma. When the beta-gamma complex is activated, the alpha subunit swaps GDP for GTP and breaks away from it. Both the alpha subunit that is linked to GTP and the beta-gamma complex can then interact with molecules further down the signaling chain to spread the signal.

Based on how similar their sequences are and how they work, GPCRs can be divided into four main groups:

• Class A (Rhodopsin-like): The biggest group of GPCRs, which includes receptors for biogenic amines, peptides, and lipids. Some examples are the beta-adrenergic receptor, which binds adrenaline and noradrenaline, and the muscarinic acetylcholine receptor, which binds acetylcholine.

• Class B (Secretin-like): Receptors for peptide hormones like glucagon, parathyroid hormone, and secretin belong to this class. Class B GPCRs have a big N-terminal domain that binds ligands and a small transmembrane domain that links with G proteins.

• Class C (Metabotropic glutamate/pheromone): Class C GPCRs have a big N-terminal domain that sticks out of the cell and makes a Venus flytrap-like structure for binding ligands. Metabotropic glutamate receptors, which are involved in neural signaling in the central nervous system, and calcium-sensing receptors, which control calcium balance, are two examples of such receptors.

• Class F (Frizzled/Smoothened): The Frizzled receptors in this class are part of the Wnt signaling pathway, and the Smoothened receptor is part of the Hedgehog signaling pathway. Both routes are very important for fetal growth and maintaining the health of tissues.

3.2 Receptor Tyrosine Kinases (RTKs)

RTKs are a group of spherical proteins that are attached to the cell membrane and work as sensors for different growth factors, cytokines, and hormones. When ligands bind to RTKs, the cytoplasmic kinase regions of their tyrosine residues become autophosphorylated. This autophosphorylation event turns on the kinase region, allowing it to phosphorylate and turn on signaling proteins like Ras, PI3K, and STATs that are further down the chain.

There are several smaller groups of RTKs, such as:

• Epidermal growth factor receptor (EGFR) family: This family has receptors for EGF, transforming growth factor-alpha (TGF-alpha), and other similar ligands.The way that EGFR signals work is important for cell growth, division, and movement.

• Insulin receptor (IR) family: The insulin receptor and the insulin-like growth factor 1 receptor (IGF-1R) are both in this family. They help control how glucose is used in the body, how cells grow and change, and how they differentiate.

• Fibroblast growth factor receptor (FGFR) family: FGFRs bind fibroblast growth factors (FGFs) and are very important for making new blood vessels, treating wounds, and developing embryos.

• Vascular endothelial growth factor receptor (VEGFR) family: VEGFRs are important for controlling angiogenesis, the process of making new blood vessels from old ones.

3.3 Ion Channels

Ion channels are spherical proteins that are attached to the cell membrane and specifically let ions like sodium, potassium, calcium, and chloride pass through. These channels are very important for many bodily functions, such as the creation and spread of electrical signals in neurons and muscle cells, the control of calcium levels inside cells, and the maintenance of ionic balance inside cells.

Ion channels can be put into different groups based on how they open and close in reaction to certain inputs. This is called the gating process. Some of the most popular kinds of ion channels are:

• Ion channels that are controlled by voltage: These channels open and close when the membrane potential changes. Some examples are voltage-gated sodium, potassium, and calcium channels, which are used by neurons and muscle cells to make action potentials.

• Ligand-gated ion channels: When certain molecules, like hormones or intracellular signaling molecules, bind to these channels, they open and close. For example, acetylcholine activates the nicotinic acetylcholine receptor at the neuromuscular junction, and glutamate activates the NMDA receptor in the central nervous system.

• Mechanosensitive ion channels: These channels open and close in reaction to factors like stress or pressure on the membrane. Some examples are the mechanosensitive channels in the hair cells of the inner ear, which help hear sound, and the Piezo channels, which help tissues sense mechanical impulses.

• Ion channels that are controlled by temperature: These channels open and close when the temperature changes. Transient receptor potential (TRP) channels are one example. These channels help us feel warmth and pain.

• Leak channels: These channels are always open, so ions can move across the membrane without stopping. They are very important for keeping the resting membrane potential of cells in good shape. One example is the potassium leak channels, which help explain why most cells have a negative resting membrane potential.

4. Structural and Mechanical Functions

4.1 Cytoskeletal Proteins

Cytoskeletal proteins are needed for cells to keep their form, structure, and dynamic qualities. Some important cytoskeletal proteins are:

• Actin: Actin strands, also called microfilaments, are important for how a cell looks, moves, and divides. They also help move things around inside the cell and send signals.

• Tubulin: Tubulin makes microtubules, which help cells divide (during mitosis and meiosis), move things inside the cell, and keep their shape.

• Intermediate filaments: Intermediate filaments provide mechanical support, protect cells from stress, and keep the shape of cells.

4.2 Motor Proteins

Motor proteins make force and move cells, like when organelles move or when a cell divides. Some important groups of motor proteins are:

• Myosins: Myosins move along actin strands and power things like muscle movement, the transport of vesicles, and cell division.

• Kinesins: Kinesins are proteins that move along microtubules. They move organelles and vesicles inside the cell and help separate the chromosomes when the cell divides.

• Dyneins: Dyneins move along microtubules and are involved in intracellular transfer, the movement of cilia and flagella, and the placement of organelles.

5. Regulation of Gene Expression

5.1 Transcription Factors

Transcription factors are proteins that bind to certain stretches of DNA and control gene expression by controlling the start of transcription or how fast it happens. They are very important for growth, cell division, and responding to messages from the outside world.

5.2 Ribosomes and Making Proteins

The ribosome is made up of rRNA and ribosomal proteins. It is a big macromolecular structure. During the process of protein production, it is in charge of turning mRNA into proteins.

6.Transport and Storage of Small Molecules

6.1 Transport Proteins

Ions, small molecules, and large molecules can move across cell membranes with the help of transport proteins. Examples include:

• on channels: Ion channels are proteins that are part of the membrane and let only certain ions pass through.

• Carrier proteins: Carrier proteins bind to certain chemicals and change their shape to move them across the cell membrane.

• ATP-binding cassette (ABC) transporters: These use the energy released when ATP breaks down to move different chemicals across the membrane.

6.2 Storage Proteins

The job of storage proteins is to store important nutrients or ions until they are needed. Examples include:

• Ferritin: Ferritin keeps iron inside cells so that poisonous iron species don’t form.

• Casein : Casein is a major protein found in milk. It is a source of amino acids for mammals that are growing.

7. Immune System Functions

7.1 Complement System

The complement system is a complicated group of proteins that work together to protect the immune system.Complement proteins help with opsonization, chemotaxis, and the formation of membrane attack complexes that kill bacteria.

7.2 Cytokines

Cytokines are small proteins that send signals between cells. They control immune reactions, inflammation, and contact between cells. They include, among other things, interferons, interleukins, and tumor necrosis factors.

8. Nuclear Receptors

Nuclear receptors are a group of intracellular proteins that work as transcription factors to control how target genes are expressed in reaction to certain ligands. Most of the time, these ligands are small molecules that don’t like water, like steroid hormones, thyroid hormones, retinoids, and fatty acids. These molecules can easily move through the cell membrane.

When a ligand binds to a nuclear receptor, the shape of the receptor changes. This allows the receptor to bind to specific DNA sequences in the promoter regions of target genes called hormone response elements (HREs). Depending on the nuclear receptor and the co-regulatory proteins that are brought in, this binding event either turns on or turns off the production of the target genes.

There are two main types of nuclear receptors:

• Type I nuclear receptors: When they are not attached to their ligands, these receptors are in the cytoplasm. When they bind to a ligand, they move to the nucleus, make two copies of themselves (usually homodimers), and bind to HREs. Some examples are the glucocorticoid receptor, the estrogen receptor, and the androgen receptor, which are all steroid hormone receptors.

• Type II nuclear receptors: These receptors are always in the nucleus and join with the retinoid X receptor (RXR) to form heterodimers. When they link to a ligand, they call in co-regulatory proteins to change how target genes are transcribed. The thyroid hormone receptor, the retinoic acid receptor, and the peroxisome proliferator-activated receptors (PPARs) are all examples.

8.1 Receptors for Enzymes

Enzyme-linked receptors are proteins that are attached to the cell membrane and have both receptor and enzyme functions. When ligands connect to these receptors, they usually undergo dimerization or other structural changes that turn on their own enzyme activity. This causes downstream signaling proteins to be phosphorylated and activated.

There are many different kinds of enzyme-linked sensors.

• Receptor tyrosine kinases: Receptor tyrosine kinases, or RTKs, are a big family of receptors that phosphorylate tyrosine residues on their own cytoplasmic regions and on signaling proteins that come after them. Some examples are the vascular endothelial growth factor receptor (VEGFR) and the epidermal growth factor receptor (EGFR).

• Receptor serine/threonine kinases: Serine and threonine sites on signaling proteins are phosphorylated by these receptors. The bone morphogenetic protein (BMP) receptor and the transforming growth factor-beta (TGF-beta) receptor are two examples.

• Receptor guanylyl cyclases: When a ligand binds to these receptors, they change GTP into cyclic GMP (cGMP), which can act as a second message to change how effector proteins work. Some examples are the guanylyl cyclase C (GC-C) receptor and the atrial natriuretic peptide (ANP) receptor.

• Receptor-like protein tyrosine phosphatases: These receptors dephosphorylate tyrosine sites on target proteins, which stops receptor tyrosine kinases from doing their jobs. Some examples are the protein tyrosine phosphatase receptor type Z (PTPRZ) and the leukocyte common antigen-related (LAR) receptor.

9. The main ways that signals are sent

These pathways are important for controlling many different biological processes, and when they don’t work right, it can lead to diseases like cancer, metabolic disorders, and brain disorders.

1. Signaling circuits that involve GPCRs

As was already said, when ligands link to G protein-coupled receptors (GPCRs), they turn on heterotrimeric G proteins. Depending on the GPCR and G protein involved, the different G protein subunits can trigger a number of different downstream signaling pathways. Some of the most important communication routes that involve GPCRs are:

• Adenylyl cyclase/cAMP/PKA pathway: Gs-coupled GPCRs start this pathway by telling the enzyme adenylyl cyclase to turn ATP into cyclic AMP (cAMP). cAMP works as a second messenger that turns on protein kinase A (PKA). PKA then phosphorylates and changes the function of different target proteins, such as ion channels, transcription factors, and metabolic enzymes. This system helps control things like cell growth, metabolism, and the production of genes.

• Phospholipase C (PLC)/IP3/DAG/PKC pathway: Gq-coupled GPCRs start this pathway by telling phospholipase C-beta (PLC-beta) to break down phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 causes calcium to be released from inside the cell, while DAG turns on protein kinase C (PKC). Both calcium and PKC control the function of target proteins like ion channels, enzymes, and transcription factors. This changes things like cell division, movement, and release.

• Rho/ROCK pathway: This pathway is turned on by G12/13-coupled GPCRs, which make Rho family GTPases like RhoA, Rac1, and Cdc42 exchange GDP for GTP. These GTPases turn on downstream effectors like Rho-associated kinase (ROCK), which control the movement of the cytoskeleton and things like cell migration, binding, and contraction.

2. Pathways that send signals through RTKs

When ligands bind to and autophosphorylate receptor tyrosine kinases (RTKs), many downstream signaling pathways are turned on. Some of the most important communication circuits that involve RTKs are:

• Ras/Raf/MEK/ERK (MAPK) pathway: When RTKs are turned on, they bind and turn on the small GTPase Ras. Ras then turns on a kinase chain that includes Raf, MEK, and ERK. This is called the MAPK pathway.When ERK is turned on, it can phosphorylate and change the function of different target proteins, like transcription factors, enzymes, and cytoskeletal proteins. This controls things like cell growth, development, and survival.

• PI3K/Akt/mTOR pathway: RTKs can also turn on phosphoinositide 3-kinase (PI3K), which makes phosphatidylinositol 3,4,5-trisphosphate (PIP3) at the plasma membrane.PIP3 finds the serine/threonine kinase Akt and turns it on. This turns on the mammalian target of rapamycin (mTOR) complex. This route is a key part of how cells grow, use energy, and stay alive.

• JAK/STAT pathway: Some RTKs, like those for cytokines and growth factors, can turn on Janus kinases (JAKs), which then phosphorylate signal transducers and activators of transcription (STATs) and turn them on. When STATs are activated, they form pairs and move to the nucleus, where they control the production of target genes that are involved in things like cell growth, division, and defense reactions.

3. Pathways that send signals through nuclear receptors

As was already said, nuclear receptors work as transcription factors that control the production of genes in reaction to certain ligands. Some of the most important communication routes that involve nuclear receptors are:

• Steroid hormone signaling: Steroid hormones like glucocorticoids, estrogens, androgens, and progestins link to their respective nuclear receptors, which then control the transcription of target genes involved in things like defense reactions, metabolism, and reproduction.

• Thyroid hormones: Thyroid hormones like triiodothyronine (T3) and thyroxine (T4) attach to the thyroid hormone receptor, which joins with the retinoid X receptor (RXR) to make a heterodimer. The protein that is attached to the dyad controls the production of target genes that are involved in things like metabolism, growth, and development.

• Retinoid signaling: Retinoids like retinoic acid and retinaldehyde link to retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which can form homodimers or heterodimers. The ligand-bound dimers control the production of target genes that are involved in things like fetal development, cell division, and defense reactions.

• Peroxisome proliferator-activated receptor (PPAR) signaling: Fatty acids and their products, as well as some man-made molecules, can turn on PPARs.PPARs join together with RXRs to make heterodimers, which control the production of target genes that are involved in fat metabolism, glucose regulation, and inflammation.

• Liver X receptor (LXR) signaling: Oxysterols, which are reduced forms of cholesterol, turn on LXRs, which are important for keeping cholesterol levels stable.LXRs join with RXRs to make heterodimers, which control the production of target genes involved in the metabolism, transport, and removal of cholesterol.

References

Alberts B, Johnson A, Lewis J, et al.The study of the cell’s molecules. Fourth printing.2002 at Garland Science in New York.

Lodish H, Berk A, Zipursky SL, et al. Molecular Cell Biology. Fourth printing. W. H. Freeman, 2000, New York.

The Cell: A Molecular Approach, by GM Cooper. 2nd print run. Sunderland (MA): Sinauer Associates; 2000.