Protein S
Belle Roetcisoender
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.
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. Proteins also have structural or mechanical functions, such as actin and myosin in muscle and the proteins in the cytoskeleton, which form a system of scaffolding that maintains 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.
Proteins may be purified from other cellular components using a variety of techniques such as ultracentrifugation, precipitation, electrophoresis, and chromatography; the advent of genetic engineering has made possible a number of methods to facilitate purification. Methods commonly used to study protein structure and function include immunohistochemistry, site-directed mutagenesis, X-ray crystallography, nuclear magnetic resonance and mass spectrometry.
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] Karl Heinrich Ritthausen extended known protein forms with the identification of glutamic acid. At the Connecticut Agricultural Experiment Station a detailed review of the vegetable proteins was compiled by Thomas Burr Osborne. Working with Lafayette Mendel and applying Liebig's law of the minimum in feeding laboratory rats, the nutritionally essential amino acids were established. The work was continued and communicated by William Cumming Rose. The understanding of proteins as polypeptides came through the work of Franz Hofmeister and Hermann Emil Fischer in 1902.[9][10] The central role of proteins as enzymes in living organisms was not fully appreciated until 1926, when James B. Sumner showed that the enzyme urease was in fact a protein.[11]
The difficulty in purifying proteins in large quantities made them very difficult for early protein biochemists to study. Hence, early studies focused on proteins that could be purified in large quantities, e.g., those of blood, egg white, various toxins, and digestive/metabolic enzymes obtained from slaughterhouses. In the 1950s, the Armour Hot Dog Co. purified 1 kg of pure 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.[4]
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.[12] Later work by Walter Kauzmann on denaturation,[13][14] based partly on previous studies by Kaj Linderstrøm-Lang,[15] contributed an understanding of protein folding and structure mediated by hydrophobic interactions.
The first protein to be 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.[16] He won the Nobel Prize for this achievement in 1958.[17]
With the development of X-ray crystallography, it became possible to sequence protein structures.[18] The first protein structures to be solved were hemoglobin by Max Perutz and myoglobin by John Kendrew, in 1958.[19][20] The use of computers and increasing computing power also supported the sequencing of complex proteins. In 1999, Roger Kornberg succeeded in sequencing the highly complex structure of RNA polymerase using high intensity X-rays from synchrotrons.[18]
Since then, cryo-electron microscopy (cryo-EM) of large macromolecular assemblies[21] 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.[18] Computational protein structure prediction of small protein domains[22] has also helped researchers to approach atomic-level resolution of protein structures.As of 2017[update], the Protein Data Bank has over 126,060 atomic-resolution structures of proteins.[23]
The number of proteins encoded in a genome roughly corresponds to the number of genes (although there may be a significant number of genes that encode RNA of protein, e.g. ribosomal RNAs). Viruses typically encode a few to a few hundred proteins, archaea and bacteria a few hundred to a few thousand, while eukaryotes typically encode a few thousand up to tens of thousands of proteins (see genome size for a list of examples).
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. Similarly, the gene ontology classifies both genes and proteins by their biological and biochemical function, but also by their intracellular location.
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 thy can be combined in many different 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).[24]
It has been estimated that average-sized bacteria contain about 2 million proteins per cell (e.g. E. coli and Staphylococcus aureus). Smaller bacteria, such as Mycoplasma or spirochetes contain fewer molecules, on the order of 50,000 to 1 million. By contrast, eukaryotic cells are larger and thus contain much more protein. For instance, yeast cells have been estimated to contain about 50 million proteins and human cells on the order of 1 to 3 billion.[32] The concentration of individual protein copies ranges from a few molecules per cell up to 20 million.[33] Not all genes coding proteins are expressed in most cells and their number depends on, for example, cell type and external stimuli. For instance, of the 20,000 or so proteins encoded by the human genome, only 6,000 are detected in lymphoblastoid cells.[34]
The size of a synthesized protein can be measured by the number of amino acids it contains and by its total molecular mass, which is normally reported in units of daltons (synonymous with atomic mass units), or the derivative unit kilodalton (kDa). The average size of a protein increases from Archaea to Bacteria to Eukaryote (283, 311, 438 residues and 31, 34, 49 kDa respectively) due to a bigger number of protein domains constituting proteins in higher organisms.[36] For instance, yeast proteins are on average 466 amino acids long and 53 kDa in mass.[28] The largest known proteins are the titins, a component of the muscle sarcomere, with a molecular mass of almost 3,000 kDa and a total length of almost 27,000 amino acids.[37]
Short proteins can also be synthesized chemically by a family of methods known as peptide synthesis, which rely on organic synthesis techniques such as chemical ligation to produce peptides in high yield.[38] Chemical synthesis allows for the introduction of non-natural amino acids into polypeptide chains, such as attachment of fluorescent probes to amino acid side chains.[39] These methods are useful in laboratory biochemistry and cell biology, though generally not for commercial applications. Chemical synthesis is inefficient for polypeptides longer than about 300 amino acids, and the synthesized proteins may not readily assume their native tertiary structure. Most chemical synthesis methods proceed from C-terminus to N-terminus, opposite the biological reaction.[40]
Many proteins are composed of several protein domains, i.e. segments of a protein that fold into distinct structural units. Domains usually also have specific functions, such as enzymatic activities (e.g. kinase) or they serve as binding modules (e.g. the SH3 domain binds to proline-rich sequences in other proteins).
Short amino acid sequences within proteins often act as recognition sites for other proteins.[42] For instance, SH3 domains typically bind to short PxxP motifs (i.e. 2 prolines [P], separated by two unspecified amino acids [x], although the surrounding amino acids may determine the exact binding specificity). Many such motifs has been collected in the Eukaryotic Linear Motif (ELM) database.
Topology of a protein describes the entanglement of the backbone and the arrangement of contacts within the folded chain.[43] Two theoretical frameworks of knot theory and Circuit topology have been applied to characterise protein topology. Being able to describe protein topology opens up new pathways for protein engineering and pharmaceutical development, and adds to our understanding of protein misfolding diseases such as neuromuscular disorders and cancer.
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