Protein

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Proteins
)

heme group
(shown in gray) with a bound oxygen molecule (red).

Proteins are large

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 archaeapyrrolysine. 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 also 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. 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

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
.

History and etymology

Proteins were recognized as a distinct class of biological molecules in the eighteenth century by

coagulate or flocculate under treatments with heat or acid.[1] Noted examples at the time included albumin from egg whites, blood serum albumin, fibrin, and wheat gluten
.

Proteins were first described by the Dutch chemist

Da.[4] Prior to "protein", other names were used, like "albumins" or "albuminous materials" (Eiweisskörper, in German).[7]

Early nutritional scientists such as the German

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

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]

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]

John Kendrew with model of myoglobin in progress

With the development of

synchrotrons.[18]

Since then,

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]

Number of proteins encoded in genomes

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).

Classification

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]

Biochemistry

CHON
elements.
Resonance structures of the peptide bond that links individual amino acids to form a protein polymer

Most proteins consist of linear

list of standard amino acids, have a great variety of chemical structures and properties; it is the combined effect of all of the amino acid side chains in a protein that ultimately determines its three-dimensional structure and its chemical reactivity.[26]
The amino acids in a polypeptide chain are linked by peptide bonds. Once linked in the protein chain, an individual amino acid is called a residue, and the linked series of carbon, nitrogen, and oxygen atoms are known as the main chain or protein backbone.[27]: 19 

The peptide bond has two

coplanar. The other two dihedral angles in the peptide bond determine the local shape assumed by the protein backbone.[27]: 31  The end with a free amino group is known as the N-terminus or amino terminus, whereas the end of the protein with a free carboxyl group is known as the C-terminus
or carboxy terminus (the sequence of the protein is written from N-terminus to C-terminus, from left to right).

The words protein, polypeptide, and

conformation
.

Interactions

Proteins can interact with many types of molecules, including

Abundance in cells

It has been estimated that average-sized

Synthesis

Biosynthesis

A ribosome produces a protein using mRNA as template
The DNA sequence of a gene encodes the amino acid sequence of a protein

Proteins are assembled from amino acids using information encoded in genes. Each protein has its own unique amino acid sequence that is specified by the

nuclear membrane into the cytoplasm, where protein synthesis then takes place. The rate of protein synthesis is higher in prokaryotes than eukaryotes and can reach up to 20 amino acids per second.[35]

The process of synthesizing a protein from an mRNA template is known as

anticodon located on a transfer RNA molecule, which carries the amino acid corresponding to the codon it recognizes. The enzyme aminoacyl tRNA synthetase "charges" the tRNA molecules with the correct amino acids. The growing polypeptide is often termed the nascent chain. Proteins are always biosynthesized from N-terminus to C-terminus.[31]
: 1002–42 

The size of a synthesized protein can be measured by the number of amino acids it contains and by its total

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]

Chemical synthesis

Short proteins can also be synthesized chemically by a family of methods known as

tertiary structure. Most chemical synthesis methods proceed from C-terminus to N-terminus, opposite the biological reaction.[40]

Structure

The crystal structure of the chaperonin, a huge protein complex. A single protein subunit is highlighted. Chaperonins assist protein folding.
triose phosphate isomerase
. Left: All-atom representation colored by atom type. Middle: Simplified representation illustrating the backbone conformation, colored by secondary structure. Right: Solvent-accessible surface representation colored by residue type (acidic residues red, basic residues blue, polar residues green, nonpolar residues white).

Most proteins

native conformation.[27]: 36  Although many proteins can fold unassisted, simply through the chemical properties of their amino acids, others require the aid of molecular chaperones to fold into their native states.[27]: 37  Biochemists often refer to four distinct aspects of a protein's structure:[27]
: 30–34 

Proteins are not entirely rigid molecules. In addition to these levels of structure, proteins may shift between several related structures while they perform their functions. In the context of these functional rearrangements, these tertiary or quaternary structures are usually referred to as "

substrate molecule to an enzyme's active site, or the physical region of the protein that participates in chemical catalysis. In solution, proteins also undergo variation in structure through thermal vibration and the collision with other molecules.[31]
: 368–75 

Molecular surface of several proteins showing their comparative sizes. From left to right are: immunoglobulin G (IgG, an antibody), hemoglobin, insulin (a hormone), adenylate kinase (an enzyme), and glutamine synthetase (an enzyme).

Proteins can be informally divided into three main classes, which correlate with typical tertiary structures:

soluble and many are enzymes. Fibrous proteins are often structural, such as collagen, the major component of connective tissue, or keratin, the protein component of hair and nails. Membrane proteins often serve as receptors or provide channels for polar or charged molecules to pass through the cell membrane.[31]
: 165–85 

A special case of intramolecular hydrogen bonds within proteins, poorly shielded from water attack and hence promoting their own

Protein domains

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).

Sequence motif

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.

Protein topology

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.

Cellular functions

Proteins are the chief actors within the cell, said to be carrying out the duties specified by the information encoded in genes.[28] With the exception of certain types of RNA, most other biological molecules are relatively inert elements upon which proteins act. Proteins make up half the dry weight of an Escherichia coli cell, whereas other macromolecules such as DNA and RNA make up only 3% and 20%, respectively.[44] The set of proteins expressed in a particular cell or cell type is known as its proteome.

The enzyme hexokinase is shown as a conventional ball-and-stick molecular model. To scale in the top right-hand corner are two of its substrates, ATP and glucose.

The chief characteristic of proteins that also allows their diverse set of functions is their ability to bind other molecules specifically and tightly. The region of the protein responsible for binding another molecule is known as the

onconase (> 1 M). Extremely minor chemical changes such as the addition of a single methyl group to a binding partner can sometimes suffice to nearly eliminate binding; for example, the aminoacyl tRNA synthetase specific to the amino acid valine discriminates against the very similar side chain of the amino acid isoleucine.[45]

Proteins can bind to other proteins as well as to small-molecule substrates. When proteins bind specifically to other copies of the same molecule, they can oligomerize to form fibrils; this process occurs often in structural proteins that consist of globular monomers that self-associate to form rigid fibers. Protein–protein interactions also regulate enzymatic activity, control progression through the cell cycle, and allow the assembly of large protein complexes that carry out many closely related reactions with a common biological function. Proteins can also bind to, or even be integrated into, cell membranes. The ability of binding partners to induce conformational changes in proteins allows the construction of enormously complex signaling networks.[31]: 830–49  As interactions between proteins are reversible, and depend heavily on the availability of different groups of partner proteins to form aggregates that are capable to carry out discrete sets of function, study of the interactions between specific proteins is a key to understand important aspects of cellular function, and ultimately the properties that distinguish particular cell types.[46][47]

Enzymes

The best-known role of proteins in the cell is as

orotate decarboxylase (78 million years without the enzyme, 18 milliseconds with the enzyme).[49]

The molecules bound and acted upon by enzymes are called

substrates. Although enzymes can consist of hundreds of amino acids, it is usually only a small fraction of the residues that come in contact with the substrate, and an even smaller fraction—three to four residues on average—that are directly involved in catalysis.[50] The region of the enzyme that binds the substrate and contains the catalytic residues is known as the active site
.

Dirigent proteins are members of a class of proteins that dictate the stereochemistry of a compound synthesized by other enzymes.[51]

Cell signaling and ligand binding

Ribbon diagram of a mouse antibody against cholera that binds a carbohydrate antigen

Many proteins are involved in the process of

tissues. Others are membrane proteins that act as receptors whose main function is to bind a signaling molecule and induce a biochemical response in the cell. Many receptors have a binding site exposed on the cell surface and an effector domain within the cell, which may have enzymatic activity or may undergo a conformational change detected by other proteins within the cell.[30]
: 251–81 

secreted into the extracellular environment or anchored in the membranes of specialized B cells known as plasma cells. Whereas enzymes are limited in their binding affinity for their substrates by the necessity of conducting their reaction, antibodies have no such constraints. An antibody's binding affinity to its target is extraordinarily high.[31]
: 275–50 

Many ligand transport proteins bind particular

Lectins typically play a role in biological recognition phenomena involving cells and proteins.[52] Receptors and hormones
are highly specific binding proteins.

hydrophobic core through which polar or charged molecules cannot diffuse. Membrane proteins contain internal channels that allow such molecules to enter and exit the cell. Many ion channel proteins are specialized to select for only a particular ion; for example, potassium and sodium channels often discriminate for only one of the two ions.[30]
: 232–34 

Structural proteins

Structural proteins confer stiffness and rigidity to otherwise-fluid biological components. Most structural proteins are

globular proteins can also play structural functions, for example, actin and tubulin are globular and soluble as monomers, but polymerize to form long, stiff fibers that make up the cytoskeleton
, which allows the cell to maintain its shape and size.

Other proteins that serve structural functions are motor proteins such as myosin, kinesin, and dynein, which are capable of generating mechanical forces. These proteins are crucial for cellular motility of single celled organisms and the sperm of many multicellular organisms which reproduce sexually. They also generate the forces exerted by contracting muscles[31]: 258–64, 272  and play essential roles in intracellular transport.

Protein evolution

A key question in molecular biology is how proteins evolve, i.e. how can

protein families, e.g. PFAM).[53] In order to prevent dramatic consequences of mutations, a gene may be duplicated before it can mutate freely. However, this can also lead to complete loss of gene function and thus pseudo-genes.[54] More commonly, single amino acid changes have limited consequences although some can change protein function substantially, especially in enzymes. For instance, many enzymes can change their substrate specificity by one or a few mutations.[55] Changes in substrate specificity are facilitated by substrate promiscuity, i.e. the ability of many enzymes to bind and process multiple substrates. When mutations occur, the specificity of an enzyme can increase (or decrease) and thus its enzymatic activity.[55] Thus, bacteria (or other organisms) can adapt to different food sources, including unnatural substrates such as plastic.[56]

Methods of study

The activities and structures of proteins may be examined in vitro, in vivo, and in silico. In vitro studies of purified proteins in controlled environments are useful for learning how a protein carries out its function: for example, enzyme kinetics studies explore the chemical mechanism of an enzyme's catalytic activity and its relative affinity for various possible substrate molecules. By contrast, in vivo experiments can provide information about the physiological role of a protein in the context of a cell or even a whole organism. In silico studies use computational methods to study proteins.

Protein purification

To perform

electrofocusing.[57]

For natural proteins, a series of purification steps may be necessary to obtain protein sufficiently pure for laboratory applications. To simplify this process, genetic engineering is often used to add chemical features to proteins that make them easier to purify without affecting their structure or activity. Here, a "tag" consisting of a specific amino acid sequence, often a series of histidine residues (a "His-tag"), is attached to one terminus of the protein. As a result, when the lysate is passed over a chromatography column containing nickel, the histidine residues ligate the nickel and attach to the column while the untagged components of the lysate pass unimpeded. A number of different tags have been developed to help researchers purify specific proteins from complex mixtures.[58]

Cellular localization

Proteins in different cellular compartments and structures tagged with green fluorescent protein (here, white)

The study of proteins in vivo is often concerned with the synthesis and localization of the protein within the cell. Although many intracellular proteins are synthesized in the

chimera consisting of the natural protein of interest linked to a "reporter" such as green fluorescent protein (GFP).[59] The fused protein's position within the cell can then be cleanly and efficiently visualized using microscopy,[60]
as shown in the figure opposite.

Other methods for elucidating the cellular location of proteins requires the use of known compartmental markers for regions such as the ER, the Golgi, lysosomes or vacuoles, mitochondria, chloroplasts, plasma membrane, etc. With the use of fluorescently tagged versions of these markers or of antibodies to known markers, it becomes much simpler to identify the localization of a protein of interest. For example,

indirect immunofluorescence will allow for fluorescence colocalization and demonstration of location. Fluorescent dyes are used to label cellular compartments for a similar purpose.[61]

Other possibilities exist, as well. For example,

While this technique does not prove colocalization of a compartment of known density and the protein of interest, it does increase the likelihood, and is more amenable to large-scale studies.

Finally, the gold-standard method of cellular localization is

immunoelectron microscopy. This technique also uses an antibody to the protein of interest, along with classical electron microscopy techniques. The sample is prepared for normal electron microscopic examination, and then treated with an antibody to the protein of interest that is conjugated to an extremely electro-dense material, usually gold. This allows for the localization of both ultrastructural details as well as the protein of interest.[63]

Through another genetic engineering application known as site-directed mutagenesis, researchers can alter the protein sequence and hence its structure, cellular localization, and susceptibility to regulation. This technique even allows the incorporation of unnatural amino acids into proteins, using modified tRNAs,[64] and may allow the rational design of new proteins with novel properties.[65]

Proteomics

The total complement of proteins present at a time in a cell or cell type is known as its proteome, and the study of such large-scale data sets defines the field of proteomics, named by analogy to the related field of genomics. Key experimental techniques in proteomics include 2D electrophoresis,[66] which allows the separation of many proteins, mass spectrometry,[67] which allows rapid high-throughput identification of proteins and sequencing of peptides (most often after in-gel digestion), protein microarrays, which allow the detection of the relative levels of the various proteins present in a cell, and two-hybrid screening, which allows the systematic exploration of protein–protein interactions.[68] The total complement of biologically possible such interactions is known as the interactome.[69] A systematic attempt to determine the structures of proteins representing every possible fold is known as structural genomics.[70]

Structure determination

Discovering the tertiary structure of a protein, or the quaternary structure of its complexes, can provide important clues about how the protein performs its function and how it can be affected, i.e. in

Cartesian coordinates for each atom in the protein.[72]

Many more gene sequences are known than protein structures. Further, the set of solved structures is biased toward proteins that can be easily subjected to the conditions required in

crystallize in preparation for X-ray crystallography. Membrane proteins and large protein complexes, by contrast, are difficult to crystallize and are underrepresented in the PDB.[73] Structural genomics initiatives have attempted to remedy these deficiencies by systematically solving representative structures of major fold classes. Protein structure prediction methods attempt to provide a means of generating a plausible structure for proteins whose structures have not been experimentally determined.[74]

Structure prediction

Constituent amino-acids can be analyzed to predict secondary, tertiary and quaternary protein structure, in this case hemoglobin containing heme units

Complementary to the field of structural genomics, protein structure prediction develops efficient mathematical models of proteins to computationally predict the molecular formations in theory, instead of detecting structures with laboratory observation.[75] The most successful type of structure prediction, known as homology modeling, relies on the existence of a "template" structure with sequence similarity to the protein being modeled; structural genomics' goal is to provide sufficient representation in solved structures to model most of those that remain.[76] Although producing accurate models remains a challenge when only distantly related template structures are available, it has been suggested that sequence alignment is the bottleneck in this process, as quite accurate models can be produced if a "perfect" sequence alignment is known.[77] Many structure prediction methods have served to inform the emerging field of protein engineering, in which novel protein folds have already been designed.[78] Also proteins (in eukaryotes ~33%) contain large unstructured but biologically functional segments and can be classified as intrinsically disordered proteins.[79] Predicting and analysing protein disorder is, therefore, an important part of protein structure characterisation.[80]

Bioinformatics

A vast array of computational methods have been developed to analyze the structure, function and evolution of proteins. The development of such tools has been driven by the large amount of genomic and proteomic data available for a variety of organisms, including the

ClustalW regarding the ancestry of modern organisms and the genes they express. The field of bioinformatics
is now indispensable for the analysis of genes and proteins.

In silico simulation of dynamical processes

A more complex computational problem is the prediction of intermolecular interactions, such as in

villin headpiece,[82] the HIV accessory protein[83] and hybrid methods combining standard molecular dynamics with quantum mechanical mathematics have explored the electronic states of rhodopsins.[84]

Beyond classical molecular dynamics,

molecular modeling by exploiting advances in GPU parallel processing and Monte Carlo
techniques.

Chemical analysis

The total nitrogen content of organic matter is mainly formed by the amino groups in proteins. The Total Kjeldahl Nitrogen (

TKN) is a measure of nitrogen widely used in the analysis of (waste) water, soil, food, feed and organic matter in general. As the name suggests, the Kjeldahl method is applied. More sensitive methods are available.[88][89]

Nutrition

Most

aspartate. If amino acids are present in the environment, microorganisms can conserve energy by taking up the amino acids from their surroundings and downregulating
their biosynthetic pathways.

In animals, amino acids are obtained through the consumption of foods containing protein. Ingested proteins are then broken down into amino acids through digestion, which typically involves denaturation of the protein through exposure to acid and hydrolysis by enzymes called proteases. Some ingested amino acids are used for protein biosynthesis, while others are converted to glucose through gluconeogenesis, or fed into the citric acid cycle. This use of protein as a fuel is particularly important under starvation conditions as it allows the body's own proteins to be used to support life, particularly those found in muscle.[90]

In animals such as dogs and cats, protein maintains the health and quality of the skin by promoting hair follicle growth and keratinization, and thus reducing the likelihood of skin problems producing malodours.[91] Poor-quality proteins also have a role regarding gastrointestinal health, increasing the potential for flatulence and odorous compounds in dogs because when proteins reach the colon in an undigested state, they are fermented producing hydrogen sulfide gas, indole, and skatole.[92] Dogs and cats digest animal proteins better than those from plants, but products of low-quality animal origin are poorly digested, including skin, feathers, and connective tissue.[92]

See also

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