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Proteins comprise 1 or more polypeptides, linear chains of amino acids linked by peptide bonds. Although cells may contain dozens of amino acids, only 20 standard amino acids are commonly found in proteins. Each amino acid is a small molecule consisting of an amino group (–NH2), a carboxyl group (–COOH), and a variable side chain, known as the R group, which determines its unique properties. The primary structure of a protein is defined by its linear sequence of amino acids in a polypeptide chain. Even with the same types and numbers of amino acids, different sequences result in different proteins. For example, Leu-Gly-Thr-Val-Arg-Asp-His is distinct from Val-His-Asp-Leu-Gly-Arg-Thr. This sequence is the first step in determining a protein’s final 3-dimensional shape. The secondary structure refers to localized folding patterns within the peptide backbone, primarily the alpha helix and beta-pleated sheet. These structures arise from hydrogen bonds between the amide N—H and carbonyl C=O groups. Importantly, side chain conformations are not part of the secondary structure. In many proteins, specific segments of the chain fold independently into compact units called domains or super-secondary structures. These structural units often carry distinct functional roles. The tertiary structure is the complete 3-dimensional arrangement of all atoms in a single polypeptide, including side chains and prosthetic groups (non-amino acid components); the structure defines the overall shape and functionality of the protein. When a protein comprises multiple polypeptide chains (called subunits), their spatial arrangement forms the quaternary structure. Noncovalent forces stabilize subunit interactions, such as hydrogen bonding, electrostatic attractions, and hydrophobic interactions. A protein's amino acid sequence, or primary structure, determines its 3-dimensional shape, which in turn dictates the protein’s function and properties. For a protein to function correctly, its structure must be precisely folded. A powerful example of the importance of primary structure is found in sickle-cell anemia, a genetic disorder caused by a single amino acid substitution in the protein hemoglobin. This small change alters hemoglobin’s shape and function, impairing its ability to bind and transport oxygen, and causing red blood cells to deform into a sickle shape.

Many diseases result from abnormalities in the amino acid composition or sequence of proteins. These mutations can alter protein folding, function, and stability, leading to various pathological outcomes. Below are 3 well-known examples: Huntington Disease Huntington disease is caused by a CAG trinucleotide repeat expansion in the HTT gene on chromosome 4. Normally, the CAG codon (which encodes glutamine) is repeated 10 to 35 times [6], but in affected individuals, it is repeated 36 or more times. The longer the repeat, the earlier the onset, and the more severe the symptoms. The abnormal protein causes degeneration of the caudate nucleus and putamen in the basal ganglia, leading to motor dysfunction (chorea), psychiatric symptoms, and progressive dementia.[7] Sickle Cell Anemia Sickle cell anemia is caused by a point mutation in the beta-globin gene, where a single base substitution changes the sixth codon from GAG (glutamic acid) to GTG (valine). This single amino acid substitution significantly alters the structure of hemoglobin.[8] The mutated hemoglobin causes red blood cells to deform into sickle shapes, leading to reduced oxygen transport, blockages in blood vessels, and symptoms such as anemia, pain episodes, organ damage, and growth delays.[9][10] Cystic Fibrosis Cystic fibrosis is caused by mutations in the CFTR gene on chromosome 7, which encodes a chloride ion channel. Over 1000 mutations have been identified, but the most common are: ΔF508, a deletion of 3 base pairs that removes phenylalanine at position 508. G551D, a point mutation that substitutes aspartate for glycine at position 551.[11] These mutations impair chloride ion transport, producing thick, sticky mucus in the lungs, pancreas, and other organs. Symptoms include chronic respiratory infections, pancreatic insufficiency, salty-tasting skin, infertility, and progressive lung disease.[12][13] p53 Mutation and Tumorigenesis

Cystic fibrosis is caused by mutations in the CFTR gene on chromosome 7, which encodes a chloride ion channel. Over 1000 mutations have been identified, but the most common are: ΔF508, a deletion of 3 base pairs that removes phenylalanine at position 508. G551D, a point mutation that substitutes aspartate for glycine at position 551.[11] These mutations impair chloride ion transport, producing thick, sticky mucus in the lungs, pancreas, and other organs. Symptoms include chronic respiratory infections, pancreatic insufficiency, salty-tasting skin, infertility, and progressive lung disease.[12][13] p53 Mutation and Tumorigenesis One of the most common genetic alterations in human cancers involves mutations in the TP53 gene, which encodes the p53 protein—a critical tumor suppressor in regulating the cell cycle, DNA repair, and apoptosis. In its normal form, p53 responds to DNA damage by halting cell division and initiating repair mechanisms or triggering programmed cell death. However, mutations in TP53, especially missense mutations that substitute 1 amino acid for another in the DNA-binding domain of the protein, can disrupt its function. For example, a common mutation substitutes arginine with histidine at codon 273 (R273H), impairing p53’s ability to bind DNA and activate target genes. Without functional p53, cells accumulate mutations unchecked, promoting uncontrolled cell proliferation and tumor development.[14][15]