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Protein

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Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells and organisms, and transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the nucleotide sequence of their genes, and which usually results in protein folding into a specific 3D structure that determines its activity.

A linear chain of amino acid residues is called a polypeptide. A protein contains at least one long polypeptide. Short polypeptides, containing less than 20–30 residues, are rarely considered to be proteins and are commonly called peptides. The individual amino acid residues are bonded together by peptide bonds and adjacent amino acid residues. The sequence of amino acid residues in a protein is defined by the sequence of a gene, which is encoded in the genetic code. In general, the genetic code specifies 20 standard amino acids; but in certain organisms the genetic code can include selenocysteine and—in certain archaea—pyrrolysine. Shortly after or even during synthesis, the residues in a protein are often chemically modified by post-translational modification, which alters the physical and chemical properties, folding, stability, activity, and ultimately, the function of the proteins. Some proteins have non-peptide groups attached, which can be called prosthetic groups or cofactors. Proteins can work together to achieve a particular function, and they often associate to form stable protein complexes.

Once formed, proteins only exist for a certain period and are then degraded and recycled by the cell's machinery through the process of protein turnover. A protein's lifespan is measured in terms of its half-life and covers a wide range. They can exist for minutes or years with an average lifespan of 1–2 days in mammalian cells. Abnormal or misfolded proteins are degraded more rapidly either due to being targeted for destruction or due to being unstable.

Like other biological macromolecules such as polysaccharides and nucleic acids, proteins are essential parts of organisms and participate in virtually every process within cells. Many proteins are enzymes that catalyse biochemical reactions and are vital to metabolism. Some proteins have structural or mechanical functions, such as actin and myosin in muscle, and the cytoskeleton's scaffolding proteins that maintain cell shape. Other proteins are important in cell signaling, immune responses, cell adhesion, and the cell cycle. In animals, proteins are needed in the diet to provide the essential amino acids that cannot be synthesized. Digestion breaks the proteins down for metabolic use.

History and etymology

Further information: History of molecular biology

Discovery and early studies

Proteins have been studied and recognized since the 1700s by Antoine Fourcroy and others,[1][2] who often collectively called them "albumins", or "albuminous materials" (Eiweisskörper, in German).[2] Gluten, for example, was first separated from wheat in published research around 1747, and later determined to exist in many plants.[1] In 1789, Antoine Fourcroy recognized three distinct varieties of animal proteins: albumin, fibrin, and gelatin.[3] Vegetable (plant) proteins studied in the late 1700s and early 1800s included gluten, plant albumin, gliadin, and legumin.[1]

Proteins were first described by the Dutch chemist Gerardus Johannes Mulder and named by the Swedish chemist Jöns Jacob Berzelius in 1838.[4][5] Mulder carried out elemental analysis of common proteins and found that nearly all proteins had the same empirical formula, C400H620N100O120P1S1.[6] He came to the erroneous conclusion that they might be composed of a single type of (very large) molecule. The term "protein" to describe these molecules was proposed by Mulder's associate Berzelius; protein is derived from the Greek word πρώτειος (proteios), meaning "primary",[7] "in the lead", or "standing in front",[2] + -in. Mulder went on to identify the products of protein degradation such as the amino acid leucine for which he found a (nearly correct) molecular weight of 131 Da.[6]

Early nutritional scientists such as the German Carl von Voit believed that protein was the most important nutrient for maintaining the structure of the body, because it was generally believed that "flesh makes flesh."[8] Around 1862, Karl Heinrich Ritthausen isolated the amino acid glutamic acid.[9] Thomas Burr Osborne compiled a detailed review of the vegetable proteins at the Connecticut Agricultural Experiment Station. Osborne, alongside Lafayette Mendel, established several nutritionally essential amino acids in feeding experiments with laboratory rats.[10] Diets lacking an essential amino acid stunts the rats' growth, consistent with Liebig's law of the minimum.[11] The final essential amino acid to be discovered, threonine, was identified by William Cumming Rose.[12]

The difficulty in purifying proteins impeded work by early protein biochemists. Proteins could be obtained in large quantities from blood, egg whites, and keratin, but individual proteins were unavailable. In the 1950s, the Armour Hot Dog Company purified 1 kg of bovine pancreatic ribonuclease A and made it freely available to scientists. This gesture helped ribonuclease A become a major target for biochemical study for the following decades.[6]

Polypeptides

polypeptide

The understanding of proteins as polypeptides, or chains of amino acids, came through the work of Franz Hofmeister and Hermann Emil Fischer in 1902.[13][14] The central role of proteins as enzymes in living organisms that catalyzed reactions was not fully appreciated until 1926, when James B. Sumner showed that the enzyme urease was in fact a protein.[15]

Linus Pauling is credited with the successful prediction of regular protein secondary structures based on hydrogen bonding, an idea first put forth by William Astbury in 1933.[16] Later work by Walter Kauzmann on denaturation,[17][18] based partly on previous studies by Kaj Linderstrøm-Lang,[19] contributed an understanding of protein folding and structure mediated by hydrophobic interactions.[20]

The first protein to have its amino acid chain sequenced was insulin, by Frederick Sanger, in 1949. Sanger correctly determined the amino acid sequence of insulin, thus conclusively demonstrating that proteins consisted of linear polymers of amino acids rather than branched chains, colloids, or cyclols.[21] He won the Nobel Prize for this achievement in 1958.[22] Christian Anfinsen's studies of the oxidative folding process of ribonuclease A, for which he won the nobel prize in 1972, solidified the thermodynamic hypothesis of protein folding, according to which the folded form of a protein represents its free energy minimum.[23][24]

Structure

John Kendrew with model of myoglobin in progress

With the development of X-ray crystallography, it became possible to determine protein structures as well as their sequences.[25] The first protein structures to be solved were hemoglobin by Max Perutz and myoglobin by John Kendrew, in 1958.[26][27] The use of computers and increasing computing power has supported the sequencing of complex proteins. In 1999, Roger Kornberg sequenced the highly complex structure of RNA polymerase using high intensity X-rays from synchrotrons.[25]

Since then, cryo-electron microscopy (cryo-EM) of large macromolecular assemblies[28] has been developed. Cryo-EM uses protein samples that are frozen rather than crystals, and beams of electrons rather than X-rays. It causes less damage to the sample, allowing scientists to obtain more information and analyze larger structures.[25] Computational protein structure prediction of small protein structural domains[29] has helped researchers to approach atomic-level resolution of protein structures. As of April 2024, the Protein Data Bank contains 181,018 X-ray, 19,809 EM and 12,697 NMR protein structures.[30]

Classification

Main articles: Protein family, Gene Ontology, and Enzyme Commission number

Proteins are primarily classified by sequence and structure, although other classifications are commonly used. Especially for enzymes the EC number system provides a functional classification scheme.[31] Similarly, gene ontology classifies both genes and proteins by their biological and biochemical function, and by their intracellular location.[32]

Sequence similarity is used to classify proteins both in terms of evolutionary and functional similarity. This may use either whole proteins or protein domains, especially in multi-domain proteins. Protein domains allow protein classification by a combination of sequence, structure and function, and they can be combined in many ways. In an early study of 170,000 proteins, about two-thirds were assigned at least one domain, with larger proteins containing more domains (e.g. proteins larger than 600 amino acids having an average of more than 5 domains).[33]