D1.2.11 Mutations that change protein structure Notes

Mutations That Change Protein Structure

1. While some mutations are harmless, others can have significant effects on an organism’s health and development.
2. Though they can occur in multiple ways, they can generally be classified into three main categories:
   1. Substitution: One base is replaced by another (also called point mutations)
   2. Insertion: One or more bases are added to the sequence.
   3. Deletion: One or more bases are removed from the sequence.

How Mutations Affect Protein Structure

1. The genetic code is a set of rules that translates mRNA sequences into amino acids, the building blocks of proteins.
2. Each group of three bases, called a codon, specifies a particular amino acid.
3. Mutations can alter this process in several ways:
   1. Silent Mutations
      1. The mutated codon still codes for the same amino acid due to the degeneracy of the genetic code.
      2. These mutations have no effect on the protein.
   2. Missense Mutations
      1. The mutated codon codes for a different amino acid.
      2. This can alter the protein’s structure and function, depending on the role of the affected amino acid.
   3. Nonsense Mutations
      1. The mutated codon becomes a stop codon, prematurely terminating protein synthesis.
      2. This usually results in a nonfunctional protein.
   4. Frameshift Mutations
      1. Insertions or deletions that are not in multiples of three shift the reading frame of the mRNA.
      2. This changes every codon downstream of the mutation, often leading to a completely nonfunctional protein.

Example

• Sickle cell disease is a classic example of how a single point mutation can dramatically affect protein structure and function.
• The Mutation
  • Normal gene: The gene for β-globin in hemoglobin has the codon GAG, which codes for glutamic acid.
  • Mutated gene: A single base substitution changes the codon to GTG, which codes for valine.
• The Consequences
  • Structural Change
    • Glutamic acid is hydrophilic, while valine is hydrophobic.
    • This substitution causes hemoglobin molecules to stick together under low oxygen conditions, forming rigid chains.
  • Cellular Impact
    • The abnormal hemoglobin distorts red blood cells into a sickle shape.
    • These sickle cells can block blood vessels, reducing blood flow and causing tissue damage.
  • Health Effects
    • Individuals with sickle cell disease experience symptoms such as pain, anemia, and increased risk of infections.

Why Some Mutations Have No Effect

Not all mutations lead to changes in protein structure:

1. Degeneracy of the Genetic Code
   1. Many amino acids are coded by multiple codons.
   2. For example, the codons $GUU$, $GUC$, $GUA$, and $GUG$ all code for valine. A mutation that changes one of these codons to another will not affect the protein.
2. Non-Coding Regions
   1. Mutations in non-coding regions of DNA, such as introns or regulatory sequences, often do not affect protein structure.
   2. However, they can still impact gene expression.
3. Functional Redundancy
   1. Some proteins can tolerate minor changes in their amino acid sequence without losing function.
   2. This is especially true if the mutation occurs in a region of the protein that is not critical for its activity.