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.

Chaperones 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

• Chemical changes made to proteins after synthesis by ribosomes alter structure, function, stability, and localization
  • Phosphorylation, glycosylation, and ubiquitination 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 kinase enzyme
  • Activates or inactivates proteins by inducing conformational changes, reversible process with phosphatases removing phosphate groups
  • Important in cell signaling (insulin signaling), metabolism (glycogen synthase), and cell cycle regulation (cyclin-dependent kinases)
• Glycosylation: Attachment of sugar molecules to proteins
  1. N-linked glycosylation on asparagine residues in ER
  2. O-linked glycosylation on serine or threonine residues in Golgi apparatus
  • Affects protein folding (quality control), stability (protection from degradation), and interactions (cell adhesion molecules)
• Ubiquitination: Covalent attachment of ubiquitin proteins to target proteins
  • Marks proteins for degradation by proteasome, can also regulate localization (nuclear transport), activity (transcription factors), and interactions (signal transduction)
  • 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
  • Heat shock proteins (Hsp60, Hsp70, Hsp90) and chaperonins (GroEL/GroES 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:
  1. Hold partially folded proteins to prevent aggregation
  2. Provide favorable environment for folding (GroEL/GroES complex creates isolated chamber)
  3. Assist refolding of stress-denatured proteins (heat shock, oxidative stress)
  4. Target misfolded proteins for degradation (CHIP co-chaperone with ubiquitin ligase activity)

Consequences of improper modifications

• Aberrant PTMs lead to protein dysfunction and disease
  • Hyperphosphorylation of tau protein associated with Alzheimer's disease forms neurofibrillary tangles and causes neuronal dysfunction
  • Abnormal glycosylation patterns in cancer cells affect cell adhesion (integrins), invasion (matrix metalloproteinases), and metastasis (selectins)
  • Impaired ubiquitination results in accumulation of misfolded proteins in neurodegenerative diseases (Parkinson's, Huntington's)
• Mutations in PTM enzymes also cause disease
  • Parkinson's 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)