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93.
Liaqat Ali Sarah A. Flowers Chunsheng Jin Eric Paul Bennet Anna-Karin H. Ekwall Niclas G. Karlsson 《Molecular & cellular proteomics : MCP》2014,13(12):3396-3409
The lubricative, heavily glycosylated mucin-like synovial glycoprotein lubricin has previously been observed to contain glycosylation changes related to rheumatoid and osteoarthritis. Thus, a site-specific investigation of the glycosylation of lubricin was undertaken, in order to further understand the pathological mechanisms involved in these diseases. Lubricin contains an serine/threonine/proline (STP)-rich domain composed of imperfect tandem repeats (EPAPTTPK), the target for O-glycosylation. In this study, using a liquid chromatography–tandem mass spectrometry approach, employing both collision-induced and electron-transfer dissociation fragmentation methods, we identified 185 O-glycopeptides within the STP-rich domain of human synovial lubricin. This showed that adjacent threonine residues within the central STP-rich region could be simultaneously and/or individually glycosylated. In addition to core 1 structures responsible for biolubrication, core 2 O-glycopeptides were also identified, indicating that lubricin glycosylation may have other roles. Investigation of the expression of polypeptide N-acetylgalactosaminyltransferase genes was carried out using cultured primary fibroblast-like synoviocytes, a cell type that expresses lubricin in vivo. This analysis showed high mRNA expression levels of the less understood polypeptide N-acetylgalactosaminyltransferase 15 and 5 in addition to the ubiquitously expressed polypeptide N-acetylgalactosaminyltransferase 1 and 2 genes. This suggests that there is a unique combination of transferase genes important for the O-glycosylation of lubricin. The site-specific glycopeptide analysis covered 82% of the protein sequence and showed that lubricin glycosylation displays both micro- and macroheterogeneity. The density of glycosylation was shown to be high: 168 sites of O-glycosylation, predominately sialylated, were identified. These glycosylation sites were focused in the central STP-rich region, giving the domain a negative charge. The more positively charged lysine and arginine residues in the N and C termini suggest that synovial lubricin exists as an amphoteric molecule. The identification of these unique properties of lubricin may provide insight into the important low-friction lubricating functions of lubricin during natural joint movement.Human diarthrodial joints are surrounded by synovial fluid (SF),1 a dense extracellular matrix fluid composed of proteins, glycoproteins, hyaluronic acid, proteoglycans, and phospholipids (1). During movement, the cartilage surfaces of the articulating joints slide over each other with an extremely low coefficient of friction that ranges from 0.0005 to 0.04 (2) and handle pressures up to ∼200 atm (3). In a healthy state, the joint surface and SF constitute a system of reduced friction that results in lifelong lubrication and wear resistance, primarily due to biolubricating molecules such as hyaluronic acid and lubricin (4). Human synovial lubricin is encoded by the proteoglycan 4 (Prg4) gene (5, 6) and is synthesized by fibroblast-like synoviocytes (FLSs) and superficial zone chondrocytes. Its 1404-amino-acid sequence contains a central mucin-like domain consisting of 59 imperfectly repeated sequences of EPAPTTPK. The O-glycosylation (in particular core 1 and sialylated core 1) of lubricin is suggested to be responsible for its lubricating properties (7), as the removal of these residues results in the loss of boundary lubrication. The molecule has also been suggested to play a key role in protecting the cartilage surface from excessive adsorption of proteins and cells (8).Arthritis results in the loss of this joint surface, leading to severe pain and a restricted range of motion. The two most common arthritic diseases, osteoarthritis (OA) and rheumatoid arthritis (RA), have different mechanisms of degradation. RA is an autoimmune systemic high inflammatory disease that increases the friction between articulating cartilage surfaces, resulting in degradation of the joint (9), whereas OA is a result of mechanical stress (10). Degeneration of the cartilage can be detected from proteoglycan fragments in the SF (11, 12). Because of the limited efficacy of available treatments, particularly for OA, understanding the biological factors related to arthritis is essential.The joints of arthritis patients, both RA and OA, have shown a down-regulation of expression and changes in glycosylation of lubricin (13). Studies using OA animal models suggest that there is a relationship between pathogenesis and the down-regulation of lubricin (9, 14, 15). This decrease in lubricin expression exacerbates the disease by accelerating the joint destruction, suggesting that certain characteristics of lubricin may be indicators of disease progression in RA and OA. Given the critical nature of lubricin glycosylation, we initiated a site-specific glycopeptide characterization of the lubricin mucin-like domain using liquid chromatography–tandem mass spectrometry with both collision-induced and electron-transfer dissociation fragmentation methods (LC-CID/ETD-MS2) after tryptic digestion of both intact and partly de-glycosylated lubricin.Collision-induced dissociation–tandem mass spectrometry (CID-MSn) of O-linked (and N-linked) glycopeptides is capable of generating sequence information both for the attached glycan (in MS2) and for the de-glycosylated peptide (in MS3), but it lacks the site-specific information of the modified amino acids (16). This is due to extensive glycosidic bond cleavage of the precursor ion in MS2 producing B/C and Y/Z ions (Domon and Costello carbohydrate fragmentation nomenclature (17)). In addition, the identification of the modified amino acids is even more difficult for peptides containing several Ser/Thr residues because of the lack of a consensus sequence for mucin-type O-glycosylation. Electron-capture dissociation and ETD are fragmentation techniques used for the site-specific characterization of protein post-translational modifications including phosphorylation (18) and glycosylation (19). Both techniques induce cleavage of the N-Cα bonds of the peptide backbone, producing c- and z-type fragment ions, while leaving the post-translational modification unaffected.In order to understand the biosynthesis of O-linked glycoproteins, one needs to link site localization of glycosylation to the expression of enzymes responsible for GalNAc-type (or mucin-type) O-glycosylation. This is necessary because the prediction of the site of GalNAc-type O-glycosylation is difficult. One reason for this is the large, redundant UDP-GalNAc:polypeptide α-N-acetylgalactosaminyltransferase (ppGalNAc T) gene family containing 20 gene-encoded isoenzymes, all possessing unique and/or overlapping substrate specificities (20, 21). These ppGalNAc Ts transfer GalNAc from the sugar nucleotide donor UDP-GalNAc to the hydroxyl groups of Ser and Thr residues in the proteins traversing the Golgi/endoplasmic reticulum. Altered protein O-glycosylation, suggested to be due to changes in the expression of distinct ppGalNAc Ts, has been reported in various disease states, including ulcerative colitis and cancer (21, 22). Thus, the connection of site-specific O-glycosylation with the responsible ppGalNAc Ts is important for understanding the functions of lubricin, as site-specific O-glycosylation has been shown to regulate the functions of proteins (23, 24) and may be involved in the pathological transformation of the joint in arthritis diseases.Although the type of glycosylation present on lubricin has been investigated previously, the site-specific glycopeptide characterization, including the analysis of the glycan types at these locations, was investigated for the first time in this study. In order to understand the nature of glycoproteins, it is essential to not only define the protein component or the glycan characteristics, but also understand how these two essential components interact. The macro- (different site occupation) and micro-heterogeneity (different glycan structure at each site) provided a heterogeneous mixture of lubricin O-linked glycopeptides that might help to explain the extraordinary properties of lubricin and how it can function as a lubricating agent in a demanding environment. 相似文献
94.
Norio Kanatsuna Jalal Taneera Fariba Vaziri-Sani Nils Wierup Helena Elding Larsson Ahmed Delli Hanna Sk?rstrand Alexander Balhuizen Hedvig Bennet Donald F. Steiner Carina T?rn Malin Fex ?ke Lernmark 《The Journal of biological chemistry》2013,288(40):29013-29023
Insulin is a major autoantigen in islet autoimmunity and progression to type 1 diabetes. It has been suggested that the insulin B-chain may be critical to insulin autoimmunity in type 1 diabetes. INS-IGF2 consists of the preproinsulin signal peptide, the insulin B-chain, and eight amino acids of the C-peptide in addition to 138 amino acids from the IGF2 gene. We aimed to determine the expression of INS-IGF2 in human pancreatic islets and autoantibodies in newly diagnosed children with type 1 diabetes and controls. INS-IGF2, expressed primarily in beta cells, showed higher levels of expression in islets from normal compared with donors with either type 2 diabetes (p = 0.006) or high HbA1c levels (p < 0.001). INS-IGF2 autoantibody levels were increased in newly diagnosed patients with type 1 diabetes (n = 304) compared with healthy controls (n = 355; p < 0.001). Displacement with cold insulin and INS-IGF2 revealed that more patients than controls had doubly reactive insulin-INS-IGF2 autoantibodies. These data suggest that INS-IGF2, which contains the preproinsulin signal peptide, the B-chain, and eight amino acids of the C-peptide may be an autoantigen in type 1 diabetes. INS-IGF2 and insulin may share autoantibody-binding sites, thus complicating the notion that insulin is the primary autoantigen in type 1 diabetes. 相似文献
95.
Barrett RD Bennet L Davidson J Dean JM George S Emerald BS Gunn AJ 《Birth defects research. Part C, Embryo today : reviews》2007,81(3):163-176
Preterm infants have a high rate of neurodevelopmental handicap. Recent imaging studies have revealed that adverse outcomes are strongly associated with reduced brain growth and neural complexity in later life. Increasing data suggest that these chronic deficits primarily reflect acute neuronal and glial injury sustained during adverse in utero events, such as exposure to severe hypoxia-ischemia and inflammation. In the present review we examine recent evidence that this chronic impairment is partly due to upregulation of physiological apoptosis, related to input deprivation, and output isolation secondary to acute white and gray matter damage and axonal injury. However, progenitor cells in the subventricular zone (SVZ) are also vulnerable to injury, and loss of part of this critical population likely further compromises brain development. Based on these concepts the impact of proposed interventions such as induced hypothermia and endogenous growth factors are likely to be complex, but potentially offer focused ways of improving the outcomes of premature birth. 相似文献
96.
97.
Nicholas R. Friedman Beatrice Lecroq Bennet Georg Fischer Eli M. Sarnat Jen‐Pan Huang L. Lacey Knowles Knowles Evan P. Economo 《Ecology and evolution》2020,10(17):9371-9383
Phenotypic traits are often integrated into evolutionary modules: sets of organismal parts that evolve together. In social insect colonies, the concepts of integration and modularity apply to sets of traits both within and among functionally and phenotypically differentiated castes. On macroevolutionary timescales, patterns of integration and modularity within and across castes can be clues to the selective and ecological factors shaping their evolution and diversification. We develop a set of hypotheses describing contrasting patterns of worker integration and apply this framework in a broad (246 species) comparative analysis of major and minor worker evolution in the hyperdiverse ant genus Pheidole. Using geometric morphometrics in a phylogenetic framework, we inferred fast and tightly integrated evolution of mesosoma shape between major and minor workers, but slower and more independent evolution of head shape between the two worker castes. Thus, Pheidole workers are evolving as a mixture of intracaste and intercaste integration and rate heterogeneity. The decoupling of homologous traits across worker castes may represent an important process facilitating the rise of social complexity. 相似文献
98.
Krenitsky VP Delgado M Nadolny L Sahasrabudhe K Ayala L Clareen SS Hilgraf R Albers R Kois A Hughes K Wright J Nowakowski J Sudbeck E Ghosh S Bahmanyar S Chamberlain P Muir J Cathers BE Giegel D Xu L Celeridad M Moghaddam M Khatsenko O Omholt P Katz J Pai S Fan R Tang Y Shirley MA Benish B Blease K Raymon H Bhagwat S Henderson I Cole AG Bennett B Satoh Y 《Bioorganic & medicinal chemistry letters》2012,22(3):1427-1432
In this Letter we describe the optimization of an aminopurine lead (1) with modest potency and poor overall kinase selectivity which led to the identification of a series of potent, selective JNK inhibitors. Improvement in kinase selectivity was enabled by introduction of an aliphatic side chain at the C-2 position. CC-359 (2) was selected as a potential clinical candidate for diseases manifested by ischemia reperfusion injury. 相似文献
99.
Keogh MJ Bennet L Drury PP Booth LC Mathai S Naylor AS Fraser M Gunn AJ 《American journal of physiology. Regulatory, integrative and comparative physiology》2012,303(3):R270-R278
Exposure to chorioamnionitis is strongly associated with neurodevelopmental disability after premature birth; however, it remains unclear whether subclinical infection affects functional EEG maturation. Chronically instrumented 103-104-day-old (0.7 gestational age: term 147 days) fetal sheep in utero were randomized to receive either gram-negative LPS by continuous low-dose infusion (100 ng iv over 24 h, followed by 250 ng/24 h for 4 days; n = 6) or the same volume of normal saline (n = 9). Arterial plasma cortisol, ACTH, and IL-6 were measured. The delta (0-3.9 Hz), theta (4-7.9 Hz), alpha (8-12.9 Hz), and beta (13-22 Hz) components of the EEG were determined by power spectral analysis. Brains were taken after 10 days for histopathology. There were no changes in blood gases, cardiovascular variables, or EEG power during LPS infusion, but a transient rise in plasma cortisol and IL-6 (P < 0.05). LPS infusion was associated with loss of the maturational increase to higher frequency activity, with reduced alpha and beta power, and greater delta power than saline controls from 6 to 10 days (P < 0.05). Histologically, LPS was associated with increased numbers of microglia and TNF-α-positive cells in the periventricular white matter and frontoparietal cortex, increased caspase-3-positive cells in white matter, but no loss of CNPase-positive oligodendrocytes, Nurr-1 subplate cells, or gyral complexity. These data suggest that low-dose endotoxin exposure can impair EEG maturation in preterm fetal sheep in association with neural inflammation but without hemodynamic disturbances or cortical injury. 相似文献
100.
Bernadette M. Dutia Stuart J. Reid Derek D. Drummond Yvonne Ligertwood Ian Bennet Willard Rietberg Ondine Silvia Michael A. Jarvis Anthony A. Nash 《PloS one》2009,4(8)