D1.2.18 Modification of polypeptides into their functional state (HL) Notes

Modification of Polypeptides into Their Functional State

1. The journey from a polypeptide to a functional proteinis a complex process that involves several modifications.
2. These changes are essential for the protein to achieve its final shape and function.

Why Are Modifications Necessary?

1. Functional Activation: Many polypeptides are inactive when first synthesized. Modifications activate them.
2. Stability and Longevity: Modifications can increase a protein’s stability, preventing degradation.
3. Specificity: Some modifications enable proteins to interact with specific molecules or perform specialized tasks.

Types of Modifications

1. Cleavage of Signal Peptides
   1. Many polypeptides have a signal peptideat one end, directing them to specific cellular locations.
   2. This peptide is often removed once the polypeptide reaches its destination.
2. Chemical Modifications
   1. Phosphorylation: Adding phosphate groups to amino acids like serine or threonine can activate or deactivate proteins.
   2. Glycosylation: Adding carbohydrate chains to proteins, often for cell recognition or stability.
   3. Methylation and Acetylation: Modifying amino acid side chains to alter protein function or interactions.
3. Folding and Stabilization
   1. Chaperone proteins assist in folding polypeptides into their correct shapes.
   2. Disulfide bonds form between cysteine residues, stabilizing the protein’s structure.
4. Formation of Quaternary Structures
   1. Some proteins consist of multiple polypeptide chains.
   2. These chains must assemble correctly to form the functional protein.
5. Conversion of Propeptides to Mature Peptides
   1. Inactive precursor proteins (propeptides) are often cleaved to produce active forms.

The Two-Stage Modification of Preproinsulin to Insulin

1. Insulin is a classic example of how polypeptides are modified to become functional proteins.
2. The process involves two main stages:
   1. Formation of Proinsulin
      1. The signal peptide is removed, leaving an 86-amino-acid chain called proinsulin.
      2. Proinsulin folds into its three-dimensional shape, stabilized by three disulfide bonds.
   2. Conversion to Mature Insulin
      1. Proinsulin is transported to the Golgi apparatus, where it undergoes further processing.
      2. A 33-amino-acid segment, known as the C-peptide, is cleaved by specific proteases.
      3. This cleavage results in two separate chains: the A-chain (21 amino acids) and the B-chain(30 amino acids).
      4. The A-chain and B-chain remain connected by the disulfide bonds formed earlier.

Why Is Insulin Modification Important?

1. Activation
   1. Preproinsulin and proinsulin are inactive.
   2. Only mature insulin can bind to insulin receptors and regulate glucose uptake.
2. Stability
   1. The disulfide bonds in insulin ensure it remains stable in the bloodstream.
3. Specificity
   1. The precise cleavage of the C-peptide ensures that the A-chain and B-chain are correctly aligned for receptor binding.

Broader Implications of Polypeptide Modifications

1. Diversity of Functions:
   1. Modifications allow a single polypeptide to perform multiple roles or adapt to different conditions.
2. Regulation:
   1. Many modifications, like phosphorylation, act as molecular switches, turning proteins on or off in response to signals.
3. Disease Prevention:
   1. Errors in modification can lead to diseases.