15.4 Post-translational modifications
3 min read•july 22, 2024
Proteins undergo chemical changes after synthesis, altering their structure and function. These post-translational modifications (PTMs) are crucial for regulating cellular processes. They allow quick responses to environmental changes without needing new protein synthesis.
are proteins that help other proteins fold correctly. They prevent aggregation and misfolding of newly made or stressed proteins. Proper folding is essential for cellular function, as a protein's 3D structure determines its role. Misfolded proteins can form toxic clumps, leading to diseases like Alzheimer's.
Post-translational Modifications and Protein Function
Post-translational modifications in protein function
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- Chemical changes made to proteins after synthesis by ribosomes alter structure, function, stability, and localization
- , , and are examples of PTMs that modify protein properties
- Crucial for regulating protein activity and cellular processes enables quick response to environmental changes or signals without requiring new protein synthesis
- Activate or inactivate proteins, change binding affinity, or target for degradation (ubiquitination) to modulate function
Types of post-translational modifications
- Phosphorylation: Addition of phosphate group to protein by enzyme
- Activates or inactivates proteins by inducing conformational changes, reversible process with phosphatases removing phosphate groups
- Important in (insulin signaling), metabolism (glycogen synthase), and cell cycle regulation (cyclin-dependent kinases)
- Glycosylation: Attachment of sugar molecules to proteins
- N-linked glycosylation on asparagine residues in ER
- O-linked glycosylation on serine or threonine residues in Golgi apparatus
- Affects (quality control), stability (protection from degradation), and interactions ()
- Ubiquitination: Covalent attachment of ubiquitin proteins to target proteins
- Marks proteins for degradation by , can also regulate localization (nuclear transport), activity (transcription factors), and interactions ()
- Involves cascade of enzymes: E1 activating, E2 conjugating, and E3 ligating enzymes specific for substrate recognition
Protein Folding and Chaperones
Chaperones in protein folding
- Proteins that assist folding of other proteins prevent aggregation and misfolding of newly synthesized or stress-denatured proteins
- (, , ) and (/ in bacteria) are examples of molecular chaperones
- Proper folding essential for cellular function as three-dimensional structure determines protein function
- Misfolded proteins can aggregate and form toxic inclusions leading to cellular dysfunction and disease (Alzheimer's, Parkinson's)
- Chaperone mechanisms:
- Hold partially folded proteins to prevent aggregation
- Provide favorable environment for folding (GroEL/GroES complex creates isolated chamber)
- Assist refolding of stress-denatured proteins (heat shock, oxidative stress)
- Target misfolded proteins for degradation ( with ubiquitin ligase activity)
Consequences of improper modifications
- Aberrant PTMs lead to protein dysfunction and disease
- Hyperphosphorylation of tau protein associated with forms neurofibrillary tangles and causes neuronal dysfunction
- Abnormal glycosylation patterns in cells affect cell adhesion (), invasion (), and metastasis ()
- Impaired ubiquitination results in accumulation of misfolded proteins in (Parkinson's, Huntington's)
- Mutations in PTM enzymes also cause disease
- caused by mutations in E3 ubiquitin ligase Parkin impairs degradation of misfolded proteins and causes mitochondrial dysfunction
- Understanding PTM role in disease enables development of targeted therapies
- Kinase inhibitors (imatinib for chronic myeloid leukemia), proteasome inhibitors (bortezomib for multiple myeloma), chaperone modulators (Hsp90 inhibitors for cancer)
Key Terms to Review (29)
Alzheimer's Disease: Alzheimer's disease is a progressive neurodegenerative disorder that primarily affects memory, thinking, and behavior. It is characterized by the accumulation of amyloid-beta plaques and tau tangles in the brain, leading to neuronal damage and cognitive decline. This disease highlights the importance of post-translational modifications, as improper modifications of proteins like tau can contribute to the development and progression of Alzheimer's.
Cancer: Cancer is a disease characterized by the uncontrolled division and growth of abnormal cells in the body, which can form tumors and invade other tissues. This process can disrupt normal cellular functions and lead to significant health issues. Various factors contribute to the development of cancer, including genetic mutations, environmental influences, and disruptions in critical cellular processes.
Cell Adhesion Molecules: Cell adhesion molecules (CAMs) are a group of proteins located on the cell surface that facilitate cell-cell and cell-extracellular matrix adhesion. They play crucial roles in maintaining tissue structure, mediating communication between cells, and regulating cellular behavior. By interacting with other cells and the extracellular environment, CAMs influence processes such as development, immune response, and wound healing.
Cell signaling: Cell signaling is the process through which cells communicate with each other to coordinate various functions and responses in an organism. This intricate system involves the reception of signals, often through specialized receptors, and the subsequent transmission of these signals within the cell, influencing cellular activities such as metabolism, gene expression, and differentiation. The effectiveness of this communication can depend on factors like membrane fluidity, carbohydrate structures, post-translational modifications, cell adhesion mechanisms, and pathways that lead to differentiation.
Chaperones: Chaperones are a group of proteins that assist in the proper folding and assembly of other proteins, ensuring that they achieve their functional three-dimensional structures. They play a crucial role in cellular processes by preventing misfolding and aggregation, which can lead to diseases. Chaperones also facilitate the transport of proteins across membranes and help refold denatured proteins, particularly during stress conditions.
Chaperonins: Chaperonins are a specific type of chaperone protein that assist in the proper folding of newly synthesized polypeptides, preventing misfolding and aggregation. These proteins form large, cylindrical complexes that create an isolated environment where proteins can fold correctly without interference from other cellular components, playing a crucial role in post-translational modifications.
Chip co-chaperone: The chip co-chaperone is a protein that functions as a co-chaperone in the heat shock protein (HSP) 70 and 90 chaperone complexes, playing a critical role in the proper folding and stabilization of other proteins. It assists in the regulation of protein homeostasis by enhancing the activity of these chaperones, particularly under stress conditions where proteins may misfold or aggregate. This involvement is essential for post-translational modifications, ensuring that proteins attain their correct functional conformations.
E1 enzyme: The e1 enzyme is a type of enzyme that plays a crucial role in the process of ubiquitination, where it activates ubiquitin, a small protein that tags other proteins for degradation. This activation is the first step in a cascade that ultimately leads to the post-translational modification of target proteins, influencing their stability, localization, and activity. Understanding the function of e1 enzymes is essential for grasping how cells regulate protein turnover and respond to various cellular signals.
E2 enzyme: The e2 enzyme, also known as an ubiquitin-conjugating enzyme, plays a crucial role in the process of ubiquitination, which is a post-translational modification that involves the addition of ubiquitin to a substrate protein. This modification affects various cellular processes, including protein degradation, cellular localization, and the modulation of protein activity. The e2 enzyme is pivotal in transferring ubiquitin from the e1 enzyme to the target protein, thus facilitating the tagging process that signals for further processing by the proteasome or other cellular pathways.
E3 enzyme: E3 enzymes, or ubiquitin ligases, are crucial components in the ubiquitin-proteasome system responsible for tagging proteins for degradation. They facilitate the transfer of ubiquitin to target proteins, which marks them for destruction by the proteasome, thereby regulating various cellular processes such as cell cycle progression, apoptosis, and DNA repair. This selective protein degradation is essential for maintaining cellular homeostasis and responding to environmental changes.
Glycosylation: Glycosylation is the biochemical process where carbohydrates, or glycans, are covalently attached to proteins or lipids, influencing their structure and function. This modification plays a critical role in various cellular functions including cell signaling, immune response, and protein stability. Glycosylation occurs predominantly in the endoplasmic reticulum and Golgi apparatus, which are essential for proper protein processing and targeting within cells.
GroEL: GroEL is a molecular chaperone protein complex that assists in the proper folding of other proteins in cells. It forms a barrel-like structure and works alongside GroES, another chaperone, to encapsulate and refold misfolded proteins, ensuring they achieve their functional conformations. This process is crucial for maintaining cellular protein homeostasis and preventing aggregation that could lead to cellular dysfunction.
Groes: Groes are specialized chaperone proteins that assist in the proper folding and assembly of other proteins, particularly those that are nascent and emerging from the ribosome. These proteins play a crucial role in ensuring that newly synthesized polypeptides achieve their correct three-dimensional structures, which is essential for their functionality within the cell.
Heat shock proteins: Heat shock proteins (HSPs) are a group of molecular chaperones that play crucial roles in the proper folding, maintenance, and protection of proteins under stress conditions, such as elevated temperatures or other cellular stresses. These proteins help prevent misfolding and aggregation, facilitating the refolding or degradation of damaged proteins to ensure cellular homeostasis.
Hsp60: Hsp60, or Heat Shock Protein 60, is a chaperonin that assists in the proper folding and assembly of proteins within the cell. It plays a crucial role in post-translational modifications by ensuring that newly synthesized polypeptides achieve their functional three-dimensional structures. This process is vital for maintaining cellular homeostasis, especially under stress conditions where misfolded proteins can accumulate.
Hsp70: Hsp70, or heat shock protein 70, is a highly conserved family of molecular chaperones that play a critical role in protein folding and protection from stress. These proteins assist in the proper folding of nascent polypeptides and refolding of misfolded proteins, particularly during conditions like heat shock, oxidative stress, and cellular damage. Hsp70 is integral to post-translational modifications as it influences protein stability and functionality after translation.
Hsp90: Hsp90, or heat shock protein 90, is a crucial molecular chaperone that assists in the proper folding and stabilization of proteins, particularly those involved in signal transduction and cellular stress responses. This protein plays a vital role in post-translational modifications by ensuring that newly synthesized proteins achieve their functional conformations, thereby influencing their activity, stability, and degradation pathways. Hsp90's activity is essential for maintaining cellular homeostasis, especially under stressful conditions, where it helps prevent protein aggregation and misfolding.
Integrins: Integrins are transmembrane proteins that play a crucial role in cell adhesion, linking the extracellular matrix (ECM) to the cytoskeleton within cells. These proteins are vital for various cellular processes, including signaling pathways, cell motility, and the maintenance of tissue architecture.
Kinase: A kinase is an enzyme that catalyzes the transfer of a phosphate group from a high-energy molecule, like ATP, to a specific substrate, usually proteins. This process is crucial for regulating many cellular activities, including signal transduction, metabolism, and cell cycle progression, primarily through post-translational modifications that alter the activity, location, or interaction of proteins within the cell.
Matrix metalloproteinases: Matrix metalloproteinases (MMPs) are a group of zinc-dependent endopeptidases that play a critical role in the remodeling of the extracellular matrix (ECM). They are involved in various physiological processes, including tissue repair and development, as well as pathological conditions such as cancer metastasis and inflammation. MMPs can degrade various ECM components, facilitating cell migration and influencing cellular behavior, which connects them to important biological processes.
Neurodegenerative diseases: Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of the structure and function of the nervous system. These diseases often involve the accumulation of misfolded proteins, disrupted intracellular transport, and alterations in cellular structures, leading to cell death and impaired communication within the nervous system.
Parkinson's Disease: Parkinson's Disease is a progressive neurodegenerative disorder that primarily affects movement, leading to symptoms such as tremors, stiffness, and balance issues. It is characterized by the death of dopamine-producing neurons in the brain, particularly in the substantia nigra, which plays a critical role in coordinating smooth and controlled movements. This condition not only has implications for motor function but also ties into broader biological concepts, including post-translational modifications that affect protein function and the potential use of stem cells for regeneration of damaged neural tissues.
Phosphatase: A phosphatase is an enzyme that catalyzes the removal of a phosphate group from a molecule, typically a protein or nucleotide. This process is essential for various cellular functions, including signal transduction and the regulation of metabolic pathways, as it can reverse the action of kinases that add phosphate groups. By removing phosphate groups, phosphatases play a crucial role in post-translational modifications, influencing protein activity, localization, and interactions.
Phosphorylation: Phosphorylation is a biochemical process that involves the addition of a phosphate group (PO₄³⁻) to a molecule, typically a protein or lipid, which can alter the molecule's function, activity, or localization. This modification plays a key role in regulating various cellular processes including signal transduction, energy metabolism, and cellular communication.
Proteasome: A proteasome is a large protein complex that plays a critical role in degrading unneeded, damaged, or misfolded proteins within cells. It ensures proper protein turnover by breaking down proteins into small peptides, which can then be further degraded into amino acids for recycling. This process is essential for maintaining cellular homeostasis and regulating various cellular processes, including cell cycle progression and responses to stress.
Protein folding: Protein folding is the process by which a protein achieves its functional three-dimensional structure from a linear chain of amino acids. This process is crucial because the specific shape of a protein determines its function within biological systems, impacting everything from enzyme activity to cellular signaling.
Selectins: Selectins are a family of cell adhesion molecules that play a critical role in the interaction between leukocytes and endothelial cells during inflammation and immune responses. They help mediate the initial steps of cell adhesion by recognizing specific carbohydrate ligands on the surface of other cells, which is vital for processes like leukocyte rolling and extravasation.
Signal transduction: Signal transduction is the process by which a cell converts an external signal into a functional response. This process involves various signaling molecules and pathways that allow cells to communicate and respond to their environment, ultimately influencing cellular activities such as gene expression, metabolism, and cell division.
Ubiquitination: Ubiquitination is the process of adding ubiquitin, a small protein, to a target protein, which can signal for its degradation, alter its activity, or change its location within the cell. This modification plays a crucial role in regulating protein turnover and maintaining cellular homeostasis, making it a vital part of post-translational modifications.