Proteins are complex molecules that perform most cellular functions, acting as enzymes, structural components, signaling molecules, and transporters. The Central Dogma of molecular biology describes the flow of genetic information from DNA to RNA to protein. The precise sequence of nucleotides in a gene determines the linear chain of amino acids, known as the primary structure. This primary structure guides the protein to fold into its unique three-dimensional shape. Since a protein’s final shape dictates its specific biological role, even a small change to the amino acid sequence can significantly impact cellular activity.
Defining the Amino Acid Change
An altered protein usually begins with a single-point mutation in the DNA sequence. If this base change results in the incorporation of a different amino acid into the protein chain, it is termed an amino acid substitution, or a missense mutation. Not every DNA change alters the protein; a silent mutation occurs when the nucleotide change still codes for the original amino acid due to the genetic code’s redundancy.
Types of Substitutions
The severity of an amino acid substitution depends on the chemical properties of the new residue compared to the original one.
A conservative substitution involves replacing an amino acid with another that shares similar characteristics, such as trading one nonpolar, hydrophobic residue for a different nonpolar, hydrophobic one. These changes often have a minimal effect on the protein’s structure and function.
In contrast, a non-conservative substitution introduces an amino acid with fundamentally different properties, such as replacing a large, charged residue with a small, uncharged one. This chemical difference is likely to disrupt the protein’s natural folding process and is associated with severe functional consequences.
A nonsense mutation is even more disruptive, as it converts an amino acid codon into a premature “stop” signal. This leads to a truncated and almost always non-functional protein.
How Substitutions Disrupt Protein Folding
Protein function relies on its precise three-dimensional configuration, achieved through a spontaneous folding process. Folding is driven by a balance of physical and chemical interactions between amino acid side chains. A substituted amino acid perturbs this internal environment, disrupting stabilizing forces. For instance, native protein structures often sequester hydrophobic residues in the core, away from the watery cellular environment.
Placing a hydrophilic, charged amino acid into this hydrophobic core creates an energetically unfavorable state. The charged residue attempts to reposition itself, forcing a major rearrangement of the local structure. This local distortion can propagate, destabilizing secondary structures like alpha-helices or beta-sheets.
When secondary structures are compromised, the entire tertiary structure is altered. The protein may fail to fold into its correct shape, leading to misfolding and aggregation. Misfolded proteins are often unstable and sticky, clumping into toxic aggregates that the cell cannot easily clear. This structural instability can result in a protein that is rapidly degraded or unable to function.
Functional Outcomes of Altered Structure
Since protein shape dictates function, structural changes inevitably lead to altered biological activity. The most frequent outcome is a complete loss of function, rendering the protein inert. This occurs when the structural change warps the protein’s active site, the pocket where it binds its target molecule. If the active site is distorted, the protein cannot interact with its partner, halting its cellular role.
In other cases, the altered structure results in altered function or specificity rather than complete failure. The substitution might change the binding site’s chemical environment, allowing the protein to interact with a different molecule or operate at an incorrect speed. This can disrupt a cellular pathway, even if the protein remains partially active. For instance, a signaling protein might remain “on” too long, sending continuous, inappropriate signals.
A rarer consequence is the gain of a novel function, where the mutation creates an entirely new, detrimental activity. This can occur when the structural change exposes a new binding surface or initiates an unregulated catalytic ability. The altered shape also affects the protein’s stability and lifespan. An unstable, misfolded protein may be quickly tagged for destruction by the cell’s quality control machinery, leading to insufficient protein levels.
Specific Examples of Amino Acid Substitution Effects
Sickle Cell Anemia illustrates how a single amino acid substitution can severely affect protein function and health. The condition results from a point mutation in the gene encoding the beta chain of hemoglobin, the oxygen-carrying protein. At the sixth position of the beta-globin chain, the hydrophilic, charged glutamic acid is replaced by the hydrophobic, non-polar valine.
This non-conservative substitution creates a sticky patch on the hemoglobin surface. When oxygen levels are low, these altered hemoglobin molecules aggregate, forming long, stiff fibers. These rigid polymers deform the flexible red blood cell into a sickle shape, obstructing blood flow in small vessels.
Another missense mutation example is the G551D substitution in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. This replaces glycine with aspartate at position 551 of the chloride channel protein. The G551D substitution decreases the channel’s open probability, meaning it fails to open correctly in response to ATP. This results in a reduction of chloride ion transport across the cell membrane, leading to the thick, sticky mucus characteristic of cystic fibrosis in organs like the lungs and pancreas.