How can an alteration in protein structure lead to a disease state? A mutation r

Question

How can an alteration in protein structure lead to a disease state? A mutation replaces a cysteine with a methionine in an antibody protein, which disrupts a critical ionic bond and results in immunodeficiency. A mutation replaces an isoleucine with an aspartic acid in a transcription factor protein, which blocks the normal folding of the protein and its function in the expression of certain genes. A valine is mutated to a leucine on a membrane channel protein, which disrupts a hydrogen bond and blocks transport of a nutrient into cells. A glutamic acid is mutated to a proline in the active site of an enzyme, which results in the loss of a critical disulfide bond needed for catalysis and blocks a step in metabolism.

Explanation / Answer

The secondary and tertiary structure of a protein dictated by its sequence, directly affects the function of the protein.

1. A mutation replacing cysteine to methionine in antibody proteins will severely affect the protein structure by disrupting the disulphide linkages (and not ionic bonds) which could result in immunodefeciency.

2. A mutation replacing isoleucine with aspartic acid in a transcription factor protein would alter the protein structure, blocking its function in the expression of certain genes. Isoleucine is a non-polar amino acid which if replaced by aspartic acid which has an acidic side chain would alter the intramolecular ionic interactions and thereby disrupting the normal folding and functioning of the protein.

3. A valine mutated to a leucine, both non-polar side chains would not significantly affect the protein structure. This alteration would lead to minor steric effects but would not affect the hydrogen bonding or transport of molecules into cells significantly.

4. The mutation of a glutamic acid residue to a proline residue in the active site of an enzyme would significantly disrupt the enzyme activity. The mode of action would not be the loss of a disulphide bond, but direct prevention of catalysis within the reaction mechanism. If the catalytic abilityof the enzyme depends on the electron donor capability of the glutamic acid residue, its mutation to a proline residue (electron acceptor) would hinder enzyme activity.

Therefore, statement 2 accurately describes the effect of an alteration in protein structure leading to a disease state.

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