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64-525: 90070 n/a ENSG00000135413 n/a Q9GZZ8 n/a NM_033277 n/a NP_150593 n/a Lacritin is a 12.3 kDa glycoprotein encoded in humans by the LACRT gene . Lacritin's discovery emerged from a screen for factors that stimulate tear protein secretion. Lacritin is a secreted protein found in tears and saliva . Lacritin also promotes tear secretion, the proliferation and survival of epithelial cells, and corneal wound healing Lacritin

128-428: A class of amphiphilic molecules, are the main components of biological membranes . The amphiphilic nature of these molecules defines the way in which they form membranes. They arrange themselves into lipid bilayers , by forming a sheet composed of two layers of lipids. Each layer forms by positioning their lypophilic chains to the same side of the layer. The two layers then stack such that their lyphphilic chains touch on

192-416: A high viscosity , for example, in egg white and blood plasma . Variable surface glycoproteins allow the sleeping sickness Trypanosoma parasite to escape the immune response of the host. The viral spike of the human immunodeficiency virus is heavily glycosylated. Approximately half the mass of the spike is glycosylation and the glycans act to limit antibody recognition as the glycans are assembled by

256-505: A predicted protein core molecular weight of 12.3 kDa, it is possible that mobility is partially retarded by lacritin's amphipathic alpha helices. Predicted p I of lacritin's core protein is 5. Lacritin is subject to crosslinking by tissue transglutaminase , thereby giving rise to lacritin multimers including dimers and trimers. Crosslinking is initiated within 1 min in vitro, requiring as little as 0.1 nM lacritin. The ~0.6 micro molar level of tissue transglutaminase estimated in human tears

320-432: A restricted group of epithelial cells (including human corneal epithelia ), and not fibroblastic, glioma, or lymphoblastic cells. Cell surface proteoglycan syndecan-1 is partly responsible. Biotinylated cell surface proteins from a lacritin-responsive cell were incubated with lacritin under conditions of physiological salt. Those that bound lacritin were sequenced by mass spectrometry . Few bound. The most prominent

384-424: A result of having both lipophilic and hydrophilic portions, some amphiphilic compounds may dissolve in water and to some extent in non-polar organic solvents . When placed in an immiscible biphasic system consisting of aqueous and organic solvents, the amphiphilic compound will partition the two phases. The extent of the hydrophobic and hydrophilic portions determines the extent of partitioning. Phospholipids ,

448-552: A single GlcNAc residue that is considered reciprocal to phosphorylation and the functions of these are likely to be an additional regulatory mechanism that controls phosphorylation-based signalling. In contrast, classical secretory glycosylation can be structurally essential. For example, inhibition of asparagine-linked, i.e. N-linked, glycosylation can prevent proper glycoprotein folding and full inhibition can be toxic to an individual cell. In contrast, perturbation of glycan processing (enzymatic removal/addition of carbohydrate residues to

512-725: Is a compound containing carbohydrate (or glycan) covalently linked to protein. The carbohydrate may be in the form of a monosaccharide, disaccharide(s). oligosaccharide(s), polysaccharide(s), or their derivatives (e.g. sulfo- or phospho-substituted). One, a few, or many carbohydrate units may be present. Proteoglycans are a subclass of glycoproteins in which the carbohydrate units are polysaccharides that contain amino sugars. Such polysaccharides are also known as glycosaminoglycans. A variety of methods used in detection, purification, and structural analysis of glycoproteins are The glycosylation of proteins has an array of different applications from influencing cell to cell communication to changing

576-438: Is complete, the amino acid sequence can be expanded upon using solid-phase peptide synthesis. Amphipathic Amphiphiles are the basis for a number of areas of research in chemistry and biochemistry, notably that of lipid polymorphism . Organic compounds containing hydrophilic groups at both ends of the molecule are called bolaamphiphilic . The micelles they form in the aggregate are prolate . The lipophilic group

640-544: Is complete. Lacripep™ is lacritin synthetic peptide 'N-94/C-6'. Glycoprotein Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification . This process is known as glycosylation . Secreted extracellular proteins are often glycosylated. In proteins that have segments extending extracellularly,

704-446: Is differentially down regulated in not only in dry eye , but also in blepharitis . Lacritin is an LFU prosecretory mitogen and survival factor with a biphasic dose response that is optimal at 1 - 10 nM for human recombinant lacritin on human cells. Higher human lacritin concentrations are optimal on rat or mouse cells or on rabbit eyes. In a recent phase I/II clinical trial, a 22 μM topical dose of 'Lacripep' applied three times daily

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768-469: Is differentially downregulated in mild to severe aqueous deficient dry eye, and in contact lens-related dry eye. In a larger trial, 95% of tears from patients with aqueous deficient dry eye were lacritin monomer deficient. Two studies that did not differentiate monomer from multimer did note any change of lacritin in dry eye. Topical treatment of eyes of dry eye mice (Aire knockout mouse model of dry eye) restored tearing, and suppressed both corneal staining and

832-453: Is for breast cancer) and gene array studies, but some breast cancers appear to display elevated expression or LACRT gene amplification. iTRAQ analysis of tears from diabetics at different stages of disease detected relatively more lacritin, lysozyme, lipophilin A, lipocalin 1, immunoglobulin lambda chain and lactotransferrin in tears of patients with diabetic retinopathy. The analysis did not distinguish lacritin monomer from polymer, and proposed

896-467: Is initiated. The upstream Gα i or Gα o signaling suggests the involvement of a G-protein-coupled receptor (GPCR). A candidate GPCR is under study. Syndecan-1 likely serves as a co-receptor. Binding lacritin may improve its GPCR affinity. Lacritin survival signaling is observed when cells are stressed. Lacritin promotes survival and homeostasis by transiently stimulating autophagy. The mechanism appears to involve lacritin stimulated acetylation of

960-530: Is likely to have been secondary to its role in host-pathogen interactions. A famous example of this latter effect is the ABO blood group system . Though there are different types of glycoproteins, the most common are N -linked and O -linked glycoproteins. These two types of glycoproteins are distinguished by structural differences that give them their names. Glycoproteins vary greatly in composition, making many different compounds such as antibodies or hormones. Due to

1024-476: Is most highly expressed in the lacrimal gland , including the accessory lacrimal gland of Wolfring. Expression is moderate in salivary glands and slight in mammary (cancer but not or rarely normal), and thyroid glands . The salivary gland expression appears to be attributable to a discrete group of unidentified ductal-like cells. Some lacritin was reported in lung bronchoalveolar lavage and plasma. In lacrimal gland, polarized lacrimal acinar cells appear to be

1088-535: Is most similar to human lacritin among all non-primate sequences examined. Moreover, it is detectable in horse tears by immunoblotting or by ELISA. Antibodies directed to the C-, but not N-, terminus of human lacritin are most effective - in keeping with the predicted conservation of the C-terminal amphipathic alpha helix necessary for cell targeting. Tissue distribution has been examined in humans and monkeys. Lacritin

1152-639: Is sufficient to promote crosslinking. Crosslinking involves the donors lysine 82 and 85 and the acceptor glutamine 106. Glutamine 106 resides within the amphipathic alpha helix near the C-terminus responsible for binding the N-terminus of syndecan-1 . Accordingly, crosslinked lacritin binds syndecan-1 poorly and is inactive. Several lacritin splice variants have been detected in Aceview, from NEIBank EST data. Lacritin-b (11.1 kDa; p I 5.3) lacks

1216-399: Is that another key element of lacritin targeting specificity is a G-protein-coupled receptor that would presumably form a cell surface targeting complex with SDC1. Involvement of a G-protein coupled receptor would explain the rapidity of lacritin signaling. Lacritin is a glycoprotein of the human tear film , and to a lesser extent of saliva, lung lavage and plasma. It is mainly produced by

1280-482: Is the only class of tear lipids apparently downregulated in dry eye. Lacritin mitogenic, survival and secretion signaling have been studied. Lacritin mitogenic signaling follows two pathways: Rapid dephosphorylation of PKCα causes it to transiently move from the cytoplasm to the area of the Golgi apparatus and peripheral nucleus. Here, it forms a complex with PKCα and PLCγ2 from which downstream mTOR and NFAT signaling

1344-450: Is through the reaction between a protected glycan and a protected Asparagine. Similarly, an O-linked glycoprotein can be formed through the addition of a glycosyl donor with a protected Serine or Threonine . These two methods are examples of natural linkage. However, there are also methods of unnatural linkages. Some methods include ligation and a reaction between a serine-derived sulfamidate and thiohexoses in water. Once this linkage

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1408-435: Is thus a multifunctional prosecretory mitogen with cell survival activity. Natural or bacterial cleavage of lacritin releases a C-terminal fragment that is bactericidal. Most lacritin is produced by the lacrimal gland , including the accessory lacrimal gland of Wolfring. Some lacritin is produced by the meibomian gland , and by epithelial cells of the conjunctiva and cornea . Together these epithelia comprise much of

1472-504: Is typically a large hydrocarbon moiety , such as a long chain of the form CH 3 (CH 2 ) n , with n > 4. The hydrophilic group falls into one of the following categories: Often, amphiphilic species have several lipophilic parts, several hydrophilic parts, or several of both. Proteins and some block copolymers are such examples. Amphiphilic compounds have lipophilic (typically hydrocarbon ) structures and hydrophilic polar functional groups (either ionic or uncharged). As

1536-542: The lacrimal gland . Some lacritin also is produced by the meibomian gland , and also by epithelial cells of the conjunctiva and cornea . The lacritin gene ( LACRT ) is one of the most transcriptionally regulated genes in the human eye . Functional studies suggest a role in epithelial renewal of some non- germative epithelia. By flowing downstream through ducts , it may generate a 'proliferative field'. Lacritin also promotes secretion (including that of lipocalin-1 and lactoferrin), cell survival and regeneration of

1600-566: The C-terminal and N-terminal halves are respectively ' ordered ' and 'disordered'. 11 - 12 predicted O-glycosylation sites populate the N-terminal half. The C-terminal amphipathic alpha helix is also the site of lacritin's only N-glycosylation site. In ' climatic droplet keratopathy ' this site is not glycosylated . Lacritin recombinantly generated in E. coli (no glycosylation) and lacritin in tears (glycosylated) differ in size with respective mobilities of ~18 and ~25 kDa by SDS-PAGE. With

1664-553: The LFU is the primary source of lacritin in the body, and the eye the main target. Dry eye is the most common eye disease , affecting 5 - 6% of the population. Prevalence rises to 6 - 9.8% in postmenopausal women, and as high as 34% in the elderly. Tears lubricate the lid and are important for the refraction of light. Tears also promote epithelial health. Only a small fraction of the estimated 1543 proteins in tears are differentially deficient or upregulated in dry eye. Lacritin monomer

1728-438: The N-terminal signal peptide and displays several predicted alpha helices , mostly in the C-terminal half. Of these, the two C-terminal ones have been confirmed by circular dichroism. The most C-terminal alpha helix is amphipathic with hydrophobic and hydrophilic residues on opposite faces. The hydrophobic face is an important syndecan-1 binding element. PONDR (Predictor of Naturally Disordered Regions) predicts that

1792-449: The agonist carbachol. When monkey lacrimal acinar cells are stressed with inflammatory cytokines (as occurs in dry eye), carbachol loses its capacity to promote the secretion of lipocalin. However, lacritin stimulates lipocalin secretion even in the presence of stress. Genomic sequencing assembled by Ensembl reveals the existence of putative lacritin orthologues in other species. Comparative genomic alignment suggests that horse lacritin

1856-473: The alpha helicity of lacritin's C-terminal amphipathic alpha helix and likely binds to the hydrophobic face. Syndecan-1 binds many growth factors through its long heparan sulfate side-chains. Yet, long heparan sulfate chains interfere with lacritin binding. Since syndecans are always decorated with heparan sulfate, this means that heparanase must be available to partially or completely cleave off heparan sulfate, allowing lacritin to bind. Indeed, no binding

1920-636: The application of all as biomarkers. Tear lacritin monomer is barely detectable in the initial stage of infection by Fusarium solani in fungal keratitis. Also down regulated are tear lipocalin-1 and cystatin S. Fungal keratitis accounts for half of all corneal ulcers in Africa and India - the primary source of blindness in these countries. Phase II clinical trial of 'Lacripep™ in Subjects With Dry Eye Associated With Primary Sjögren's Syndrome' (NCT03226444)

1984-516: The bioactive lacritin synthetic peptides 'N-104', 'N-94' and 'N-94/C-6' from lacritin's C-terminus. Protease inhibitor studies suggest that processing of lacritin into C-terminal proteoforms requires a variety of tear proteases including cathepsin B , calpain , alanyl amino peptidase , arginyl aminopeptidase , MMP9 , MMP10 , cathepsin G , plasma kallikrein , plasmin , thrombin and trypsin . C-terminal proteoforms, like intact lacritin, are selectively deficient in dry eye tears. Lacritin targets

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2048-542: The body is mucins , which are secreted in the mucus of the respiratory and digestive tracts. The sugars when attached to mucins give them considerable water-holding capacity and also make them resistant to proteolysis by digestive enzymes. Glycoproteins are important for white blood cell recognition. Examples of glycoproteins in the immune system are: H antigen of the ABO blood compatibility antigens. Other examples of glycoproteins include: Soluble glycoproteins often show

2112-449: The cationic face) appear to contribute to binding. Point mutagenesis of lacritin has narrowed the ligation site. This novel heparanase mechanism appears at first glance to be poor for ocular health since heparanase release from invading lymphocytes in the corneal stroma is inflammatory. Yet heparanase is a normal secretory product of the corneal epithelium. Lacritin-dependent mitogenesis is inhibitable by pertussis toxin ,. The implication

2176-483: The cell, causing a decrease in drug effectiveness. Therefore, being able to inhibit this behavior would decrease P-glycoprotein interference in drug delivery, making this an important topic in drug discovery. For example, P-Glycoprotein causes a decrease in anti-cancer drug accumulation within tumor cells, limiting the effectiveness of chemotherapies used to treat cancer. Hormones that are glycoproteins include: Quoting from recommendations for IUPAC: A glycoprotein

2240-536: The corneal epithelium after wounding. Three times daily topical treatment with C-terminal lacritin synthetic peptide 'Lacripep' (also known as 'N-94/C-6') at a 4 μM concentration regenerated corneal nerves and the ocular surface epithelium in the mouse Aire-/- dry eye model. This raises the possibility that lacritin may have clinical applications in the treatment of dry eye , the most common eye disease . It also may be beneficial in promoting healing after LASIK or PRK surgery. Recent studies suggest that lacritin monomer

2304-1006: The description of the small (40,42 aa) plaque-forming (aggregative) Aβ fragments. Antimicrobial peptides (AMPs) are another class of amphiphilic molecules, a big data analysis showed that amphipathicity best distinguished between AMPs with and without anti-gram-negative bacteria activities. The higher amphipathicity, the better chances for AMPs possessing antibacterial and antifungal dual activities. There are several examples of molecules that present amphiphilic properties: Hydrocarbon -based surfactants are an example group of amphiphilic compounds. Their polar region can be either ionic , or non-ionic. Some typical members of this group are: sodium dodecyl sulfate ( anionic ), benzalkonium chloride ( cationic ), cocamidopropyl betaine ( zwitterionic ), and 1-octanol (long-chain alcohol, non-ionic). Many biological compounds are amphiphilic: phospholipids , cholesterol , glycolipids , fatty acids , bile acids , saponins , local anaesthetics, etc. Soap

2368-497: The dose optimum less effective. Other mitogens share this property. However, in secretion assays using monkey lacritin on monkey lacrimal acinar cells, the dose response appears to be sigmoidal with increasing lipocalin or lactoferrin secretion through a narrow 0.1, 0.3 and 1 μM dose range. Lacritin flows downstream from the lacrimal gland through ducts onto the eye . Artificial depletion of lacritin from normal human tears revealed that tears lacking lacritin are unable to promote

2432-414: The extracellular segments are also often glycosylated. Glycoproteins are also often important integral membrane proteins , where they play a role in cell–cell interactions. It is important to distinguish endoplasmic reticulum-based glycosylation of the secretory system from reversible cytosolic-nuclear glycosylation. Glycoproteins of the cytosol and nucleus can be modified through the reversible addition of

2496-420: The glycan), which occurs in both the endoplasmic reticulum and Golgi apparatus , is dispensable for isolated cells (as evidenced by survival with glycosides inhibitors) but can lead to human disease (congenital disorders of glycosylation) and can be lethal in animal models. It is therefore likely that the fine processing of glycans is important for endogenous functionality, such as cell trafficking, but that this

2560-535: The host cell and so are largely 'self'. Over time, some patients can evolve antibodies to recognise the HIV glycans and almost all so-called 'broadly neutralising antibodies (bnAbs) recognise some glycans. This is possible mainly because the unusually high density of glycans hinders normal glycan maturation and they are therefore trapped in the premature, high-mannose, state. This provides a window for immune recognition. In addition, as these glycans are much less variable than

2624-432: The hydrophobic part into the lipid membrane, while exposing the hydrophilic part to the aqueous medium, altering their physical behavior and sometimes disrupting them. Aβ proteins form antiparallel β sheets which are strongly amphiphilic, and which aggregate to form toxic oxidative Aβ fibrils. Aβ fibrils themselves are composed of amphiphilic 13-mer modular β sandwiches separated by reverse turns. Hydropathic waves optimize

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2688-561: The inside and their polar groups are outside facing the surrounding aqueous media. Thus the inside of the bilayer sheet is a non-polar region sandwiched between the two polar sheets. Although phospholipids are the principal constituents of biological membranes, there are other constituents, such as cholesterol and glycolipids , which are also included in these structures and give them different physical and biological properties. Many other amphiphilic compounds, such as pepducins , strongly interact with biological membranes by insertion of

2752-547: The lacrimal functional unit (LFU). Dry eye is the most common disease of the LFU. A growing number of studies suggest that lacritin may be differentially downregulated in dry eye, including contact lens-related dry eye. Topical lacritin promotes tearing in rabbit preclinical studies. In the Aire knockout mouse model of dry eye (considered similar to human Sjogren's syndrome), topical lacritin restores pilocarpine-induced tearing, largely eliminates lissamine green staining and reduces

2816-428: The master protector. Dry eye tears are subject to premature collapse, as are normal human tears artificially depleted of C-terminal proteoforms. In both cases, stability is largely restored by spiking in synthetic lacritin peptides N-94 or N-94/C-6 as proxy C-terminal proteoforms. Each peptide inserts rapidly into (O-acyl)-omega-hydroxy fatty acid ( OAHFA ) thought to reside at the aqueous lipid boundary in tears. OAHFA

2880-469: The most common cell line used for recombinant glycoprotein production is the Chinese hamster ovary line. However, as technologies develop, the most promising cell lines for recombinant glycoprotein production are human cell lines. The formation of the link between the glycan and the protein is key element of the synthesis of glycoproteins. The most common method of glycosylation of N-linked glycoproteins

2944-706: The most common. Monosaccharides commonly found in eukaryotic glycoproteins include: The sugar group(s) can assist in protein folding , improve proteins' stability and are involved in cell signalling. The critical structural element of all glycoproteins is having oligosaccharides bonded covalently to a protein. There are 10 common monosaccharides in mammalian glycans including: glucose (Glc), fucose (Fuc), xylose (Xyl), mannose (Man), galactose (Gal), N- acetylglucosamine (GlcNAc), glucuronic acid (GlcA), iduronic acid (IdoA), N-acetylgalactosamine (GalNAc), sialic acid , and 5- N-acetylneuraminic acid (Neu5Ac). These glycans link themselves to specific areas of

3008-445: The most prolific lacritin producers, as evidenced by strong staining of secretory granules in keeping with lacritin release after carbachol stimulation. Carbachol-dependent release involves PKC and calcium signaling. Some lacritin is produced by the meibomian gland , and also by epithelial cells of the conjunctiva and cornea that together with lacrimal gland comprise much of the lacrimal functional unit (LFU). Viewed collectively,

3072-471: The production of the protein. Glycosylation is a process that roughly half of all human proteins undergo and heavily influences the properties and functions of the protein. Within the cell, glycosylation occurs in the endoplasmic reticulum . There are several techniques for the assembly of glycoproteins. One technique utilizes recombination . The first consideration for this method is the choice of host, as there are many different factors that can influence

3136-488: The protein amino acid chain. The two most common linkages in glycoproteins are N -linked and O -linked glycoproteins. An N -linked glycoprotein has glycan bonds to the nitrogen containing an asparagine amino acid within the protein sequence. An O -linked glycoprotein has the sugar is bonded to an oxygen atom of a serine or threonine amino acid in the protein. Glycoprotein size and composition can vary largely, with carbohydrate composition ranges from 1% to 70% of

3200-487: The purposes of this field of study is to determine which proteins are glycosylated and where in the amino acid sequence the glycosylation occurs. Historically, mass spectrometry has been used to identify the structure of glycoproteins and characterize the carbohydrate chains attached. The unique interaction between the oligosaccharide chains have different applications. First, it aids in quality control by identifying misfolded proteins. The oligosaccharide chains also change

3264-419: The sequence SIVEKSILTE. Lacritin-c (10.7 kDa; p I 4.6) displays a novel C-terminus that should be incapable of binding syndecan-1, and lacks cell survival activity. Splice variants are proteoforms . Proteoforms include proteolytically processed forms of lacritin. Top down mass spec sequencing revealed that human tears contain five N- and forty-two different C-terminal lacritin-a proteoforms. Some approximate

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3328-467: The size of inflammatory foci in lacrimal glands. Lacritin monomer deficiency in tears of patients with blepharitis was also reported. Blepharitis is an inflammation of the eyelid often associated with dry eye. In climatic droplet keratopathy , N119 appears to be un- glycosylated . Also a normal breast cancer localization reported by some has not been replicated in Unigene (the ' mammary gland ' hit

3392-638: The size of inflammatory foci in the lacrimal gland. Lacritin cell targeting is dependent on the cell surface heparan sulfate proteoglycan syndecan-1 (SDC1). Binding utilizes an enzyme-regulated 'off-on' switch in which active epithelial heparanase (HPSE) cleaves off heparan sulfate to expose a binding site in the N-terminal region of syndecan-1's core protein. A G-protein-coupled receptor (GPCR) then appears to be ligated. Targeted cells signal to NFAT and mTOR if conditions are suitable for proliferation, or to AKT and FOXO3 under conditions of stress. Lacritin consists of 119 amino acids after cleavage of

3456-405: The solubility and polarity of the proteins that they are bonded to. For example, if the oligosaccharide chains are negatively charged, with enough density around the protein, they can repulse proteolytic enzymes away from the bonded protein. The diversity in interactions lends itself to different types of glycoproteins with different structures and functions. One example of glycoproteins found in

3520-493: The success of glycoprotein recombination such as cost, the host environment, the efficacy of the process, and other considerations. Some examples of host cells include E. coli, yeast, plant cells, insect cells, and mammalian cells. Of these options, mammalian cells are the most common because their use does not face the same challenges that other host cells do such as different glycan structures, shorter half life, and potential unwanted immune responses in humans. Of mammalian cells,

3584-436: The survival of ocular surface cells stressed with inflammatory cytokines. Human dry eye tears also lack this activity. However, dry eye tears supplemented with lacritin are fully protective. Similarly, tears artificially depleted of lacritin are deficient in bactericidal activity. The antibody used to deplete lacritin also depletes C-terminal proteoforms. These observations suggest that among all tear proteins, lacritin may be

3648-403: The thermal stability and the folding of proteins. Due to the unique abilities of glycoproteins, they can be used in many therapies. By understanding glycoproteins and their synthesis, they can be made to treat cancer, Crohn's Disease , high cholesterol, and more. The process of glycosylation (binding a carbohydrate to a protein) is a post-translational modification , meaning it happens after

3712-543: The total mass of the glycoprotein. Within the cell, they appear in the blood, the extracellular matrix , or on the outer surface of the plasma membrane, and make up a large portion of the proteins secreted by eukaryotic cells. They are very broad in their applications and can function as a variety of chemicals from antibodies to hormones. Glycomics is the study of the carbohydrate components of cells. Though not exclusive to glycoproteins, it can reveal more information about different glycoproteins and their structure. One of

3776-626: The transcription factor FOXO3. Acetylated FOXO3 serves as a ligand for the autophagic mediator ATG101. Lacritin also promotes coupling of FOXO1 (that becomes acetylated with stress) with autophagic mediator ATG7. In the absence of lacritin, no coupling is observed. Thus acetylation alone is likely insufficient for FOXO1-ATG7 ligation, unlike an initial claim. Lacritin also restores oxidative phosphorylation and other metabolic events to rescue cells from stress. Lacritin stimulated secretion of tear proteins lipocalin and lactoferrin from monkey lacrimal acinar cells does not appear to be mediated by Ca, unlike

3840-402: The underlying protein, they have emerged as promising targets for vaccine design. P-glycoproteins are critical for antitumor research due to its ability block the effects of antitumor drugs. P-glycoprotein, or multidrug transporter (MDR1), is a type of ABC transporter that transports compounds out of cells. This transportation of compounds out of cells includes drugs made to be delivered to

3904-400: The wide array of functions within the body, interest in glycoprotein synthesis for medical use has increased. There are now several methods to synthesize glycoproteins, including recombination and glycosylation of proteins. Glycosylation is also known to occur on nucleo cytoplasmic proteins in the form of O -GlcNAc . There are several types of glycosylation, although the first two are

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3968-437: Was detected from cells lacking heparanase after siRNA depletion. Binding was restored by spiking in exogenous heparanase or heparitinase. Thus, heparanase regulates lacritin function as an 'on-switch'. Exposed 3-O sulfated groups on heparanase-cleaved heparan sulfate (that likely interacts with the cationic face of lacritin's C-terminal amphipathic alpha helix), and an N-terminal chondroitin sulfate chain (likely also binds to

4032-411: Was effective at two weeks in primary Sjogren's Syndrome patients with an eye dryness score greater than 60, a score indicative of moderate to severe dry eye. Both corneal fluorescein staining and the symptom of burning/stinging were reduced. In keeping with a biphasic dose response, the 44 μM dose was largely ineffective. A biphasic dose response has a bell-shaped curve , with doses lower or higher than

4096-457: Was syndecan-1 (SDC1). In confirmatory pull-down assays, binding was not shared with family members syndecan-2 or syndecan-4 , indicating that the protein core (and not the negatively charged heparan sulfate side-chains) was the main site of binding. Further analysis narrowed the site to syndecan-1's N-terminal 51 amino acids, and subsequently to the N-terminal sequence GAGAL that is conserved in syndecan-1's from different species. GAGAL promotes

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