Amino acid substitutions can significantly alter protein function by changing its structure and/or interactions.
Here's a breakdown of how amino acid substitutions affect protein function:
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Altering Protein Structure:
- Folding: The amino acid sequence dictates how a protein folds into its 3D structure. Substituting an amino acid with different properties (e.g., hydrophobic to hydrophilic) can disrupt folding patterns, leading to misfolding or instability.
- Active Site Changes: If a substitution occurs within or near the active site of an enzyme, it can directly affect substrate binding and catalytic activity. This can lead to reduced efficiency or complete loss of function.
- Domain Interactions: Amino acid substitutions can disrupt interactions between different domains within a protein, affecting its overall conformation and function.
- Protein-Protein Interactions: Changes on the protein surface can alter the way it binds to other proteins, disrupting signaling pathways or complex formation.
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Impact on RNA structure: Synonymous mutations (mutations that do not change the amino acid sequence) can still affect protein function by altering RNA structural elements. (Fishman et al., 2009; Hu et al., 2009; Tuplin et al., 2004).
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Impact on ARFP: Synonymous mutations can also lead to amino acid changes in the alternative ribosomal frame shift protein (ARFP) (Fishman et al., 2009; Hu et al., 2009; Tuplin et al., 2004).
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Types of Amino Acid Substitutions and Their Effects:
- Conservative Substitutions: Replacing an amino acid with one that has similar properties (e.g., leucine for isoleucine) may have a minimal effect on protein function, as the overall structure and properties are largely maintained.
- Non-Conservative Substitutions: Replacing an amino acid with one that has very different properties (e.g., glycine for tryptophan) is more likely to have a significant impact on protein function, as it can disrupt the protein's structure and interactions.
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Examples:
- Sickle Cell Anemia: A classic example is sickle cell anemia, where a single amino acid substitution (glutamic acid to valine) in hemoglobin causes the protein to aggregate, leading to deformed red blood cells and various health problems.
- Enzyme Deficiencies: Many genetic diseases are caused by amino acid substitutions that disrupt the function of specific enzymes, leading to metabolic disorders.
In summary, amino acid substitutions can significantly alter protein function by affecting its structure, interactions, and stability. The impact of a substitution depends on the specific amino acid change, its location within the protein, and the protein's overall role.
