A T cell, or T lymphocyte, is a type of lymphocyte that plays a central role in cell-mediated immunity. T cells can be distinguished from other lymphocytes, such as B cells and natural killer cells, by the presence of a T-cell receptor on the cell surface, they are called T cells. The several subsets of T cells each have a distinct function; the majority of human T cells, termed alpha beta T cells, rearrange their alpha and beta chains on the cell receptor and are part of the adaptive immune system. Specialized gamma delta T cells, have invariant T-cell receptors with limited diversity, that can present antigens to other T cells and are considered to be part of the innate immune system. Effector cells are the superset of all the various T cell types that respond to a stimulus, such as co-stimulation; this includes helper, killer and other T cell types. Memory cells are their opposite counterpart that are longer lived to target future infections as necessary. T helper cells assist other white blood cells in immunologic processes, including maturation of B cells into plasma cells and memory B cells, activation of cytotoxic T cells and macrophages.
These cells are known as CD4+ T cells because they express the CD4 glycoprotein on their surfaces. Helper T cells become activated when they are presented with peptide antigens by MHC class II molecules, which are expressed on the surface of antigen-presenting cells. Once activated, they divide and secrete small proteins called cytokines that regulate or assist in the active immune response; these cells can differentiate into one of several subtypes, including TH1, TH2, TH3, TH17, TH9, or TFH, which secrete different cytokines to facilitate different types of immune responses. Signalling from the APC directs T cells into particular subtypes. Cytotoxic T cells destroy virus-infected cells and tumor cells, are implicated in transplant rejection; these cells are known as CD8+ T cells since they express the CD8 glycoprotein at their surfaces. These cells recognize their targets by binding to antigen associated with MHC class I molecules, which are present on the surface of all nucleated cells. Through IL-10, other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state, which prevents autoimmune diseases.
Antigen-naïve T cells expand and differentiate into memory and effector T cells after they encounter their cognate antigen within the context of an MHC molecule on the surface of a professional antigen presenting cell. Appropriate co-stimulation must be present at the time of antigen encounter for this process to occur. Memory T cells were thought to belong to either the effector or central memory subtypes, each with their own distinguishing set of cell surface markers. Subsequently, numerous new populations of memory T cells were discovered including tissue-resident memory T cells, stem memory TSCM cells, virtual memory T cells; the single unifying theme for all memory T cell subtypes is that they are long-lived and can expand to large numbers of effector T cells upon re-exposure to their cognate antigen. By this mechanism they provide the immune system with "memory" against encountered pathogens. Memory T cells may be either CD4+ or CD8+ and express CD45RO. Memory T cell subtypes: Central memory T cells express CD45RO, C-C chemokine receptor type 7, L-selectin.
Central memory T cells have intermediate to high expression of CD44. This memory subpopulation is found in the lymph nodes and in the peripheral circulation.. Effector memory T cells lack expression of CCR7 and L-selectin, they have intermediate to high expression of CD44. These memory T cells lack lymph node-homing receptors and are thus found in the peripheral circulation and tissues. TEMRA stands for terminally differentiated effector memory cells re-expressing CD45RA, a marker found on naive T cells. Tissue resident memory T cells occupy tissues without recirculating. One cell surface marker, associated with TRM is the integrin αeβ7. Virtual memory T cells differ from the other memory subsets in that they do not originate following a strong clonal expansion event. Thus, although this population as a whole is abundant within the peripheral circulation, individual virtual memory T cell clones reside at low frequencies. One theory is. Although CD8 virtual memory T cells were the first to be described, it is now known that CD4 virtual memory cells exist.
Regulatory T cells are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress autoreactive T cells that escaped the process of negative selection in the thymus. Suppressor T cells along with Helper T cells can collectively be called Regulatory T cells due to their regulatory functions. Two major classes of CD4 + Treg cells have been described -- FOXP3 − Treg cells. Regulatory T cells can develop either during normal development in the thymus, are known as thymic Treg cells, or can be induced peripherally and are called peripherally derived Treg cel
Protein Data Bank
The Protein Data Bank is a database for the three-dimensional structural data of large biological molecules, such as proteins and nucleic acids. The data obtained by X-ray crystallography, NMR spectroscopy, or cryo-electron microscopy, submitted by biologists and biochemists from around the world, are accessible on the Internet via the websites of its member organisations; the PDB is overseen by an organization called the Worldwide Protein Data Bank, wwPDB. The PDB is a key in areas such as structural genomics. Most major scientific journals, some funding agencies, now require scientists to submit their structure data to the PDB. Many other databases use protein structures deposited in the PDB. For example, SCOP and CATH classify protein structures, while PDBsum provides a graphic overview of PDB entries using information from other sources, such as Gene ontology. Two forces converged to initiate the PDB: 1) a small but growing collection of sets of protein structure data determined by X-ray diffraction.
In 1969, with the sponsorship of Walter Hamilton at the Brookhaven National Laboratory, Edgar Meyer began to write software to store atomic coordinate files in a common format to make them available for geometric and graphical evaluation. By 1971, one of Meyer's programs, SEARCH, enabled researchers to remotely access information from the database to study protein structures offline. SEARCH was instrumental in enabling networking, thus marking the functional beginning of the PDB; the Protein Data Bank was announced in October 1971 in Nature New Biology as a joint venture between Cambridge Crystallographic Data Centre, UK and Brookhaven National Laboratory, USA. Upon Hamilton's death in 1973, Tom Koeztle took over direction of the PDB for the subsequent 20 years. In January 1994, Joel Sussman of Israel's Weizmann Institute of Science was appointed head of the PDB. In October 1998, the PDB was transferred to the Research Collaboratory for Structural Bioinformatics; the new director was Helen M. Berman of Rutgers University.
In 2003, with the formation of the wwPDB, the PDB became an international organization. The founding members are PDBe, RCSB, PDBj; the BMRB joined in 2006. Each of the four members of wwPDB can act as deposition, data processing and distribution centers for PDB data; the data processing refers to the fact that annotate each submitted entry. The data are automatically checked for plausibility; the PDB database is updated weekly. The PDB holdings list is updated weekly; as of 17 October 2018, the breakdown of current holdings is as follows: 120,052 structures in the PDB have a structure factor file. 9,734 structures have an NMR restraint file. 3,486 structures in the PDB have a chemical shifts file. 2,531 structures in the PDB have a 3DEM map file deposited in EM Data BankThese data show that most structures are determined by X-ray diffraction, but about 10% of structures are now determined by protein NMR. When using X-ray diffraction, approximations of the coordinates of the atoms of the protein are obtained, whereas estimations of the distances between pairs of atoms of the protein are found through NMR experiments.
Therefore, the final conformation of the protein is obtained, in the latter case, by solving a distance geometry problem. A few proteins are determined by cryo-electron microscopy; the significance of the structure factor files, mentioned above, is that, for PDB structures determined by X-ray diffraction that have a structure file, the electron density map may be viewed. The data of such structures is stored on the "electron density server". In the past, the number of structures in the PDB has grown at an exponential rate, passing the 100 registered structures milestone in 1982, the 1,000 in 1993, the 10,000 in 1999, the 100,000 in 2014. However, since 2007, the rate of accumulation of new protein structures appears to have plateaued; the file format used by the PDB was called the PDB file format. This original format was restricted by the width of computer punch cards to 80 characters per line. Around 1996, the "macromolecular Crystallographic Information file" format, mmCIF, an extension of the CIF format started to be phased in.
MmCIF is now the master format for the PDB archive. An XML version of this format, called PDBML, was described in 2005; the structure files can be downloaded in any of these three formats. In fact, individual files are downloaded into graphics packages using web addresses: For PDB format files, use, e.g. http://www.pdb.org/pdb/files/4hhb.pdb.gz or http://pdbe.org/download/4hhb For PDBML files, use, e.g. http://www.pdb.org/pdb/files/4hhb.xml.gz or http://pdbe.org/pdbml/4hhbThe "4hhb" is the PDB identifier. Each structure published in PDB receives a four-character alphanumeric identifier, its PDB ID; the structure files may be viewed using one of several free and open source computer programs, including Jmol, Pymol, VMD, Rasmol. Other non-free, shareware programs
Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non-sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which are the basic units of information for DNA, it represents about 8% of the total DNA in human cells. It was the last completed chromosome, sequenced two decades after the beginning of the Human Genome Project; the following are some of the gene count estimates of human chromosome 1. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies. Among various projects, the collaborative consensus coding sequence project takes an conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes; the following is a partial list of genes on human chromosome 1. For complete list, see the link in the infobox on the right. DENN1B hypothesized to be related to asthma Partial list of the genes located on p-arm of human chromosome 1: Partial list of the genes located on q-arm of human chromosome 1: There are 890 known diseases related to this chromosome.
Some of these diseases are hearing loss, Alzheimer's disease and breast cancer. Rearrangements and mutations of chromosome 1 are prevalent in cancer and many other diseases. Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, in regions where no function is evident. Complete monosomy is invariably lethal before birth. Complete trisomy is lethal within days after conception; some partial deletions and partial duplications produce birth defects. The following diseases are some of those related to genes on chromosome 1: National Institutes of Health. "Chromosome 1". Genetics Home Reference. Retrieved 2017-05-06. "Final genome'chapter' published". BBC NEWS. 2006-05-18. Retrieved 2017-05-06. "Chromosome 1". Human Genome Project Information Archive 1990–2003. Retrieved 2017-05-06
A base pair is a unit consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA and RNA. Dictated by specific hydrogen bonding patterns, Watson–Crick base pairs allow the DNA helix to maintain a regular helical structure, subtly dependent on its nucleotide sequence; the complementary nature of this based-paired structure provides a redundant copy of the genetic information encoded within each strand of DNA. The regular structure and data redundancy provided by the DNA double helix make DNA well suited to the storage of genetic information, while base-pairing between DNA and incoming nucleotides provides the mechanism through which DNA polymerase replicates DNA and RNA polymerase transcribes DNA into RNA. Many DNA-binding proteins can recognize specific base-pairing patterns that identify particular regulatory regions of genes. Intramolecular base pairs can occur within single-stranded nucleic acids.
This is important in RNA molecules, where Watson–Crick base pairs permit the formation of short double-stranded helices, a wide variety of non-Watson–Crick interactions allow RNAs to fold into a vast range of specific three-dimensional structures. In addition, base-pairing between transfer RNA and messenger RNA forms the basis for the molecular recognition events that result in the nucleotide sequence of mRNA becoming translated into the amino acid sequence of proteins via the genetic code; the size of an individual gene or an organism's entire genome is measured in base pairs because DNA is double-stranded. Hence, the number of total base pairs is equal to the number of nucleotides in one of the strands; the haploid human genome is estimated to be about 3.2 billion bases long and to contain 20,000–25,000 distinct protein-coding genes. A kilobase is a unit of measurement in molecular biology equal to 1000 base pairs of DNA or RNA; the total amount of related DNA base pairs on Earth is estimated at 5.0×1037 and weighs 50 billion tonnes.
In comparison, the total mass of the biosphere has been estimated to be as much as 4 TtC. Hydrogen bonding is the chemical interaction. Appropriate geometrical correspondence of hydrogen bond donors and acceptors allows only the "right" pairs to form stably. DNA with high GC-content is more stable than DNA with low GC-content. But, contrary to popular belief, the hydrogen bonds do not stabilize the DNA significantly; the larger nucleobases and guanine, are members of a class of double-ringed chemical structures called purines. Purines are complementary only with pyrimidines: pyrimidine-pyrimidine pairings are energetically unfavorable because the molecules are too far apart for hydrogen bonding to be established. Purine-pyrimidine base-pairing of AT or GC or UA results in proper duplex structure; the only other purine-pyrimidine pairings would be AC and GT and UG. The GU pairing, with two hydrogen bonds, does occur often in RNA. Paired DNA and RNA molecules are comparatively stable at room temperature, but the two nucleotide strands will separate above a melting point, determined by the length of the molecules, the extent of mispairing, the GC content.
Higher GC content results in higher melting temperatures. On the converse, regions of a genome that need to separate — for example, the promoter regions for often-transcribed genes — are comparatively GC-poor. GC content and melting temperature must be taken into account when designing primers for PCR reactions; the following DNA sequences illustrate pair double-stranded patterns. By convention, the top strand is written from the 5' end to the 3' end. A base-paired DNA sequence: ATCGATTGAGCTCTAGCG TAGCTAACTCGAGATCGCThe corresponding RNA sequence, in which uracil is substituted for thymine in the RNA strand: AUCGAUUGAGCUCUAGCG UAGCUAACUCGAGAUCGC Chemical analogs of nucleotides can take the place of proper nucleotides and establish non-canonical base-pairing, leading to errors in DNA replication and DNA transcription; this is due to their isosteric chemistry. One common mutagenic base analog is 5-bromouracil, which resembles thymine but can base-pair to guanine in its enol form. Other chemicals, known as DNA intercalators, fit into the gap between adjacent bases on a single strand and induce frameshift mutations by "masquerading" as a base, causing the DNA replication machinery to skip or insert additional nucleotides at the intercalated site.
Most intercalators are known or suspected carcinogens. Examples include ethidium acridine. An unnatural base pair is a designed subunit of DNA, created in a laboratory and does not occur in nature. DNA sequences have been described which use newly created nucleobases to form a third base pair, in addition to the two ba
TNF receptor-associated factor 2 is a protein that in humans is encoded by the TRAF2 gene. The protein encoded by this gene is a member of the TNF receptor associated factor protein family. TRAF proteins associate with, mediate the signal transduction from members of the TNF receptor superfamily; this protein directly interacts with TNF receptors, forms complexes with other TRAF proteins. TRAF2 is required for TNF-alpha-mediated activation of MAPK8/JNK and NF-κB; the protein complex formed by TRAF2 and TRAF1 interacts with the IAP family members cIAP1 and cIAP2, functions as a mediator of the anti-apoptotic signals from TNF receptors. The interaction of this protein with TRADD, a TNF receptor associated apoptotic signal transducer, ensures the recruitment of IAPs for the direct inhibition of caspase activation. CIAP1 can ubiquitinate and induce the degradation of this protein, thus potentiate TNF-induced apoptosis. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of only one transcript has been determined.
TRAF2 has been shown to interact with: Model organisms have been used in the study of TRAF2 function. A conditional knockout mouse line called Traf2tm1aWtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping
Proteins are large biomolecules, or macromolecules, consisting of 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, transporting molecules from one location to another. Proteins differ from one another in their sequence of amino acids, dictated by the nucleotide sequence of their genes, which results in protein folding into a specific three-dimensional 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 considered to be proteins and are called peptides, or sometimes oligopeptides; 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, encoded in the genetic code.
In general, the genetic code specifies 20 standard amino acids. Shortly after or during synthesis, the residues in a protein are chemically modified by post-translational modification, which alters the physical and chemical properties, stability and the function of the proteins. Sometimes proteins have non-peptide groups attached, which can be called prosthetic groups or cofactors. Proteins can work together to achieve a particular function, they associate to form stable protein complexes. Once formed, proteins only exist for a certain period and are degraded and recycled by the cell's machinery through the process of protein turnover. A protein's lifespan covers a wide range, they can exist for years with an average lifespan of 1 -- 2 days in mammalian cells. Abnormal or misfolded proteins are degraded more 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 every process within cells.
Many proteins are enzymes that are vital to metabolism. Proteins 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, 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 use in the metabolism. Proteins may be purified from other cellular components using a variety of techniques such as ultracentrifugation, precipitation and chromatography. Methods used to study protein structure and function include immunohistochemistry, site-directed mutagenesis, X-ray crystallography, nuclear magnetic resonance and mass spectrometry. Most proteins consist of linear polymers built from series of up to 20 different L-α- amino acids. All proteinogenic amino acids possess common structural features, including an α-carbon to which an amino group, a carboxyl group, a variable side chain are bonded.
Only proline differs from this basic structure as it contains an unusual ring to the N-end amine group, which forces the CO–NH amide moiety into a fixed conformation. The side chains of the standard amino acids, detailed in the list of standard amino acids, have a great variety of chemical structures and properties; 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, the linked series of carbon and oxygen atoms are known as the main chain or protein backbone; the peptide bond has two resonance forms that contribute some double-bond character and inhibit rotation around its axis, so that the alpha carbons are coplanar. The other two dihedral angles in the peptide bond determine the local shape assumed by the protein backbone; 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 words protein and peptide are a little ambiguous and can overlap in meaning. Protein is used to refer to the complete biological molecule in a stable conformation, whereas peptide is reserved for a short amino acid oligomers lacking a stable three-dimensional structure. However, the boundary between the two is not well defined and lies near 20–30 residues. Polypeptide can refer to any single linear chain of amino acids regardless of length, but implies an absence of a defined conformation. Proteins can interact with many types of molecules, including with other proteins, with lipids, with carboyhydrates, with DNA, it has been estimated. 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 pro
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are proteins, but in non-protein coding genes such as transfer RNA or small nuclear RNA genes, the product is a functional RNA; the process of gene expression is used by all known life—eukaryotes and utilized by viruses—to generate the macromolecular machinery for life. Several steps in the gene expression process may be modulated, including the transcription, RNA splicing and post-translational modification of a protein. Gene regulation gives the cell control over structure and function, is the basis for cellular differentiation and the versatility and adaptability of any organism. Gene regulation may serve as a substrate for evolutionary change, since control of the timing and amount of gene expression can have a profound effect on the functions of the gene in a cell or in a multicellular organism. In genetics, gene expression is the most fundamental level at which the genotype gives rise to the phenotype, i.e. observable trait.
The genetic code stored in DNA is "interpreted" by gene expression, the properties of the expression give rise to the organism's phenotype. Such phenotypes are expressed by the synthesis of proteins that control the organism's shape, or that act as enzymes catalysing specific metabolic pathways characterising the organism. Regulation of gene expression is thus critical to an organism's development. A gene is a stretch of DNA. Genomic DNA consists of two antiparallel and reverse complementary strands, each having 5' and 3' ends. With respect to a gene, the two strands may be labeled the "template strand," which serves as a blueprint for the production of an RNA transcript, the "coding strand," which includes the DNA version of the transcript sequence.. The production of the RNA copy of the DNA is called transcription, is performed in the nucleus by RNA polymerase, which adds one RNA nucleotide at a time to a growing RNA strand as per the complementarity law of the bases; this RNA is complementary to the template 3' → 5' DNA strand, itself complementary to the coding 5' → 3' DNA strand.
Therefore, the resulting 5' → 3' RNA strand is identical to the coding DNA strand with the exception that Thymines are replaced with uracils in the RNA. A coding DNA strand reading "ATG" is indirectly transcribed through the “TAC” in the non-coding template strand as "AUG" in the mRNA. In prokaryotes, transcription is carried out by a single type of RNA polymerase, which needs a DNA sequence called a Pribnow box as well as a sigma factor to start transcription. In eukaryotes, transcription is performed by three types of RNA polymerases, each of which needs a special DNA sequence called the promoter and a set of DNA-binding proteins—transcription factors—to initiate the process. RNA polymerase. RNA polymerase II transcribes all protein-coding genes but some non-coding RNAs. Pol II includes a C-terminal domain, rich in serine residues; when these residues are phosphorylated, the CTD binds to various protein factors that promote transcript maturation and modification. RNA polymerase III transcribes 5S rRNA, transfer RNA genes, some small non-coding RNAs.
Transcription ends. While transcription of prokaryotic protein-coding genes creates messenger RNA, ready for translation into protein, transcription of eukaryotic genes leaves a primary transcript of RNA, which first has to undergo a series of modifications to become a mature mRNA; these include 5' capping, set of enzymatic reactions that add 7-methylguanosine to the 5' end of pre-mRNA and thus protect the RNA from degradation by exonucleases. The m7G cap is bound by cap binding complex heterodimer, which aids in mRNA export to cytoplasm and protect the RNA from decapping. Another modification is 3' polyadenylation, they occur if polyadenylation signal sequence is present in pre-mRNA, between protein-coding sequence and terminator. The pre-mRNA is first cleaved and a series of ~200 adenines are added to form poly tail, which protects the RNA from degradation. Poly tail is bound by multiple poly-binding proteins necessary for mRNA export and translation re-initiation. A important modification of eukaryotic pre-mRNA is RNA splicing.
The majority of eukaryotic pre-mRNAs consist of alternating segments called introns. During the process of splicing, an RNA-protein catalytical complex known as spliceosome catalyzes two transesterification reactions, which remove an intron and release it in form of lariat structure, splice neighbouring exons together. In certain cases, some introns or exons can be either removed or retained in mature mRNA; this so-called alternative splicing creates series of different transcripts originating from a single gene. Because these transcripts can be translated into different proteins, splicing extends the complexity of eukaryotic gene expression. Extensive RNA processing may be an evolutionary advantage made possible by the nucleus of eukaryotes. In prokaryotes and translation happen together, whilst in eukaryotes, the nuclear membrane separates the two processes, giving time for RNA processing to