Misplaced Pages

#437562

42-497: 2KB9 , 2VJ2 , 4CBZ , 4CC0 , 4CC1 , 4XI7 , 5BO1 182 16449 ENSG00000101384 ENSMUSG00000027276 P78504 Q9QXX0 NM_000214 NM_013822 NP_000205 NP_038850 Jagged1 ( JAG1 ) is one of five cell surface proteins ( ligands ) that interact with four receptors in the mammalian Notch signaling pathway . The Notch signaling pathway is a highly conserved pathway that functions to establish and regulate cell fate decisions in many organ systems. Once

84-502: A cartilaginous or bony gill arch, which helps to maintain the gill's surface area . Bony fish (osteichthyans, mostly teleost ray-finned fish ) have four pairs of arches, cartilaginous fish (chondrichthyans) have five to seven pairs, and the more basal jawless fish ("agnathans") have up to seven. The Cambrian ancestors of vertebrates no doubt had more gill arches, as some of their chordate relatives have more than 50 pairs of gills. In amphibians and some primitive bony fish,

126-485: A chemical environment for the ligand and receptor to adapt, and thus accept or reject each other as partners. Radioligands are radioisotope labeled compounds used in vivo as tracers in PET studies and for in vitro binding studies. The interaction of ligands with their binding sites can be characterized in terms of a binding affinity. In general, high-affinity ligand binding results from greater attractive forces between

168-546: A cystine-rich region, 16 EGF-like repeats , a DSL domain, and finally a signal peptide totaling 1218 amino acids in length over 26 coding exons . The JAG1 protein encoded by JAG1 is the human homolog of the Drosophila jagged protein. Human JAG1 is one of five ligands for receptors in the NOTCH signaling pathway which helps to determine cellular fate and is active during many developmental stages. The extracellular component of

210-456: A fixed concentration of reference ligand is determined. The K i value can be estimated from IC 50 through the Cheng Prusoff equation . Ligand affinities can also be measured directly as a dissociation constant (K d ) using methods such as fluorescence quenching , isothermal titration calorimetry or surface plasmon resonance . Low-affinity binding (high K i level) implies that

252-499: A hydrophobic protein (e.g. lipid-gated ion channels ) determining the affinity is complicated by non-specific hydrophobic interactions. Non-specific hydrophobic interactions can be overcome when the affinity of the ligand is high. For example, PIP2 binds with high affinity to PIP2 gated ion channels. Bivalent ligands consist of two drug-like molecules (pharmacophores or ligands) connected by an inert linker. There are various kinds of bivalent ligands and are often classified based on what

294-410: A ligand is adequate to maximally occupy a ligand-binding site and trigger a physiological response. Receptor affinity is measured by an inhibition constant or K i value, the concentration required to occupy 50% of the receptor. Ligand affinities are most often measured indirectly as an IC 50 value from a competition binding experiment where the concentration of a ligand required to displace 50% of

336-447: A limited phenotype (involving the eye), mice haploinsufficient for both Jag1 and Notch2 present with the ALGS phenotype. Conditional gene knockout mouse models with Jag1 mutations targeted to the portal vein mesenchyme , endothelium , and cranial neural crest all exhibit features classic to those in individuals with ALGS, highlighting the role of this tissue type in disease origins ALGS

378-453: A patient phenotype, it is thought that haploinsufficiency for JAG1 is the likely disease mechanism of action. Although individuals can have a range of mutation types in JAG1 , all of the known mutations lead to loss of the function of one copy, and, there is no correlation between mutation type or location and disease severity. Though individuals with ALGS have several body systems affected, there

420-423: A purely sensory organ, often have very reduced hyoid systems. The primitive arrangement is 7 (possibly 8) arches, each consisting of the same series of paired (left and right) elements. order from dorsal-most (highest) to ventral-most (lowest), these elements are the pharyngobranchial, epibranchial, ceratobranchial, hypobranchial, and basibranchial. The pharyngobranchials may articulate with the neurocranium , while

462-402: A receptor can be characterized both in terms of how much physiological response can be triggered (that is, the efficacy ) and in terms of the concentration of the agonist that is required to produce the physiological response (often measured as EC 50 , the concentration required to produce the half-maximal response). High-affinity ligand binding implies that a relatively low concentration of

SECTION 10

#1732923069438

504-472: A receptor protein composes the functional state. Ligands include substrates , inhibitors , activators , signaling lipids , and neurotransmitters . The rate of binding is called affinity , and this measurement typifies a tendency or strength of the effect. Binding affinity is actualized not only by host–guest interactions, but also by solvent effects that can play a dominant, steric role which drives non-covalent binding in solution. The solvent provides

546-423: A relatively high concentration of a ligand is required before the binding site is maximally occupied and the maximum physiological response to the ligand is achieved. In the example shown to the right, two different ligands bind to the same receptor binding site. Only one of the agonists shown can maximally stimulate the receptor and, thus, can be defined as a full agonist . An agonist that can only partially activate

588-504: A tagged ligand and an untagged ligand. Real-time based methods, which are often label-free, such as surface plasmon resonance , dual-polarization interferometry and multi-parametric surface plasmon resonance (MP-SPR) can not only quantify the affinity from concentration based assays; but also from the kinetics of association and dissociation, and in the later cases, the conformational change induced upon binding. MP-SPR also enables measurements in high saline dissociation buffers thanks to

630-454: A unique optical setup. Microscale thermophoresis (MST), an immobilization-free method was developed. This method allows the determination of the binding affinity without any limitation to the ligand's molecular weight. For the use of statistical mechanics in a quantitative study of the ligand-receptor binding affinity, see the comprehensive article on the configurational partition function . Binding affinity data alone does not determine

672-474: A worldwide grid of well over a million ordinary PCs was harnessed for cancer research in the project grid.org , which ended in April 2007. Grid.org has been succeeded by similar projects such as World Community Grid , Human Proteome Folding Project , Compute Against Cancer and Folding@Home . Branchial arches Branchial arches or gill arches are a series of paired bony / cartilaginous "loops" behind

714-634: Is a subset of individuals with JAG1 mutations who present with tetralogy of fallot / pulmonary stenosis that do not show the other clinical signs of the syndrome. Given the variable expressivity of the disease, there may be other genetic or environmental modifiers present beyond the original JAG1 mutation. More recently, JAG1 expression changes have been implicated in many types of cancer. Specifically, up regulation of JAG1 has been correlated with both poor overall breast cancer survival rates and an enhancement of tumor proliferation in adrenocortical carcinoma patients. This article incorporates text from

756-407: Is an autosomal dominant multi-system disorder affecting several body systems including the liver , heart , skeleton , eye , facial structure, kidneys and vascular system . The most clinically significant concerns stem from liver, heart, vascular or renal problems. Mutations in JAG1 were first discovered to be responsible for ALGS by researchers at The Children's Hospital of Philadelphia and

798-557: Is important to note that not all tissues where JAG1 is expressed are affected in ALGS. More recently JAG1 expression has been found to be altered in breast cancer and adrenocortical carcinoma patients. Mouse models where the Jag1 gene is turned off in certain tissues (conditional knockout mouse models) have been used to study the role of Jag1 in many tissue specific areas. While homozygous deletions of Jag1 have been shown to be embryonic lethal in mice, and heterozygous deletions may show only

840-457: Is modified for similar reasons. It is often used in buccal pumping and often plays a role in tongue protrusion for prey capture. In species with highly specialized ballistic tongue movements such as chameleons or some plethodontid salamanders , the hyoid system is highly modified for this purpose, while it is often hypertrophied in species which use suction feeding . Species such as snakes and monitor lizards, whose tongue has evolved into

882-641: The National Institutes of Health in 1997. Patients who are clinically consistent with the disorder usually have a mutation in JAG1 (94%), while a smaller 2% have a mutation in NOTCH2 . Over half of individuals with mutations in the gene did not inherit it from either parent, and thus have a de novo mutation. JAG1 mutation types include protein truncating ( splice site , frameshift , and nonsense ), missense , and whole gene deletions accounting for 80%, 7%, and 12% respectively. Since all mutation types lead to

SECTION 20

#1732923069438

924-506: The United States National Library of Medicine , which is in the public domain . Ligand (biochemistry) Binding occurs by intermolecular forces , such as ionic bonds , hydrogen bonds and Van der Waals forces . The association or docking is actually reversible through dissociation . Measurably irreversible covalent bonding between a ligand and target molecule is atypical in biological systems. In contrast to

966-461: The larvae bear external gills branching out from the gill arches. These regress upon adulthood , their function taken over by the gills proper in fish, or by lungs (which are homologous to swim bladders ) and cutaneous respiration in most amphibians. Some neotenic amphibians (such as the axolotl ) retain the external larval gills in adulthood, the complex internal gill system as seen in fish apparently being irrevocably lost very early in

1008-441: The pancreas , heart , placenta , prostate , lung , kidney , thymus , testis , and leucocytes in the adult. In a developing embryo JAG1 expression is concentrated around the pulmonary artery , mesocardium, distal cardic outflow tract, major arteries, metanephros , branchial arches , pancreas , the portal vein , and otocyst . Generally, JAG1 expression patterns correlate with organ systems affected in ALGS, although it

1050-414: The throat ( pharyngeal cavity ) of fish , which support the fish gills . As chordates , all vertebrate embryos develop pharyngeal arches , though the eventual fate of these arches varies between taxa . In all jawed fish (gnathostomes), the first arch pair (mandibular arches) develops into the jaw , the second gill arches (the hyoid arches) develop into the hyomandibular complex (which supports

1092-582: The JAG1 protein physically interacts with its respective Notch receptor. This interaction kicks off a cascade of proteolytic cleavages leading to the original NOTCH intracellular domain being trafficked into the nucleus of the cell leading to the activation of different target genes. In situ hybridization and conditional gene knockout studies have helped to demonstrate the role JAG1 plays in development and its effects on different organ systems. In humans, JAG1 has broad expression in many tissue types including

1134-456: The JAG1-NOTCH (receptor-ligand) interactions take place, a cascade of proteolytic cleavages is triggered resulting in activation of the transcription for downstream target genes. Located on human chromosome 20 , the JAG1 gene is expressed in multiple organ systems in the body and causes the autosomal dominant disorder Alagille syndrome (ALGS) resulting from loss of function mutations within

1176-400: The back of the jaw and the front of the gill series), and the remaining posterior arches (simply called branchial arches) support the gills. In tetrapods , a mostly terrestrial clade evolved from lobe-finned fish , many pharyngeal arch elements are lost, including the gill arches. In amphibians and reptiles , only the oral jaws and a hyoid apparatus remains, and in mammals and birds

1218-433: The binding energy can be used to cause a conformational change in the receptor, resulting in altered behavior for example of an associated ion channel or enzyme . A ligand that can bind to and alter the function of the receptor that triggers a physiological response is called a receptor agonist . Ligands that bind to a receptor but fail to activate the physiological response are receptor antagonists . Agonist binding to

1260-440: The definition of ligand in metalorganic and inorganic chemistry , in biochemistry it is ambiguous whether the ligand generally binds at a metal site, as is the case in hemoglobin . In general, the interpretation of ligand is contextual with regards to what sort of binding has been observed. Ligand binding to a receptor protein alters the conformation by affecting the three-dimensional shape orientation. The conformation of

1302-411: The evolution of tetrapods . The branchial system is typically used for respiration and/or feeding. Many fish have modified posterior gill arches into pharyngeal jaws , often equipped with specialized pharyngeal teeth for handling particular prey items (long, sharp teeth in carnivorous moray eels compared to broad, crushing teeth in durophagous black carp). In amphibians and reptiles, the hyoid arch

JAG1 - Misplaced Pages Continue

1344-1159: The evolution, function, allostery and folding of protein compexes. A privileged scaffold is a molecular framework or chemical moiety that is statistically recurrent among known drugs or among a specific array of biologically active compounds. These privileged elements can be used as a basis for designing new active biological compounds or compound libraries. Main methods to study protein–ligand interactions are principal hydrodynamic and calorimetric techniques, and principal spectroscopic and structural methods such as Other techniques include: fluorescence intensity, bimolecular fluorescence complementation, FRET (fluorescent resonance energy transfer) / FRET quenching surface plasmon resonance, bio-layer interferometry , Coimmunopreciptation indirect ELISA, equilibrium dialysis, gel electrophoresis, far western blot, fluorescence polarization anisotropy, electron paramagnetic resonance, microscale thermophoresis , switchSENSE . The dramatically increased computing power of supercomputers and personal computers has made it possible to study protein–ligand interactions also by means of computational chemistry . For example,

1386-401: The gene. JAG1 has also been designated as CD339 ( cluster of differentiation 339). JAG1 was first identified as a ligand that was able to activate notch receptors when the rat gene Jagged encoding a protein homolog was cloned in 1995. The structure of the JAG1 protein includes a small intracellular component, a transmembrane motif, proceeded by an extracellular region containing

1428-406: The hyoid is simplified further to support the tongue and floor of the mouth . In mammals, the first and second pharyngeal arches also give rise to the auditory ossicles . Most vertebrates are aquatic and breathe with gills , where water comes in contact for exchanging dissolved oxygen before flowing out through a series of openings ( gill slits ) to the outside. Each gill is supported by

1470-400: The left and right basibranchials connect to each other (often fusing into a single bone). When part of the hyoid arch, the names of the bones are altered by replacing "-branchial" with "-hyal", thus "ceratobranchial" becomes "ceratohyal". Amniotes do not have gills . The gill arches form as pharyngeal arches during embryogenesis , and lay the basis of essential structures such as jaws ,

1512-409: The ligand and its receptor while low-affinity ligand binding involves less attractive force. In general, high-affinity binding results in a higher occupancy of the receptor by its ligand than is the case for low-affinity binding; the residence time (lifetime of the receptor-ligand complex) does not correlate. High-affinity binding of ligands to receptors is often physiologically important when some of

1554-417: The number of protein chains they bind. "Monodesmic" ligands (μόνος: single, δεσμός: binding) are ligands that bind a single protein chain, while "polydesmic" ligands (πολοί: many) are frequent in protein complexes, and are ligands that bind more than one protein chain, typically in or near protein interfaces. Recent research shows that the type of ligands and binding site structure has profound consequences for

1596-1119: The opioid receptor system. Bivalent ligands were also reported early on by Micheal Conn and coworkers for the gonadotropin-releasing hormone receptor . Since these early reports, there have been many bivalent ligands reported for various G protein-coupled receptor (GPCR) systems including cannabinoid, serotonin, oxytocin, and melanocortin receptor systems, and for GPCR - LIC systems ( D2 and nACh receptors ). Bivalent ligands usually tend to be larger than their monovalent counterparts, and therefore, not 'drug-like' as in Lipinski's rule of five . Many believe this limits their applicability in clinical settings. In spite of these beliefs, there have been many ligands that have reported successful pre-clinical animal studies. Given that some bivalent ligands can have many advantages compared to their monovalent counterparts (such as tissue selectivity, increased binding affinity, and increased potency or efficacy), bivalents may offer some clinical advantages as well. Ligands of proteins can be characterized also by

1638-442: The overall potency of a drug or a naturally produced (biosynthesized) hormone. Potency is a result of the complex interplay of both the binding affinity and the ligand efficacy. Ligand efficacy refers to the ability of the ligand to produce a biological response upon binding to the target receptor and the quantitative magnitude of this response. This response may be as an agonist , antagonist , or inverse agonist , depending on

1680-462: The pharmacophores target. Homobivalent ligands target two of the same receptor types. Heterobivalent ligands target two different receptor types. Bitopic ligands target an orthosteric binding sites and allosteric binding sites on the same receptor. In scientific research, bivalent ligands have been used to study receptor dimers and to investigate their properties. This class of ligands was pioneered by Philip S. Portoghese and coworkers while studying

1722-401: The physiological response is called a partial agonist . In this example, the concentration at which the full agonist (red curve) can half-maximally activate the receptor is about 5 x 10 Molar (nM = nanomolar ). Binding affinity is most commonly determined using a radiolabeled ligand, known as a tagged ligand. Homologous competitive binding experiments involve binding competition between

JAG1 - Misplaced Pages Continue

1764-457: The physiological response produced. Selective ligands have a tendency to bind to very limited kinds of receptor, whereas non-selective ligands bind to several types of receptors. This plays an important role in pharmacology , where drugs that are non-selective tend to have more adverse effects , because they bind to several other receptors in addition to the one generating the desired effect. For hydrophobic ligands (e.g. PIP2) in complex with

#437562