ABSTRACT
Progress in improving patient outcomes and advancing therapeutics in chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) is hampered by phenotypic heterogeneity and variable responsiveness to clinical interventions that are not fully explained by currently held disease paradigms for COPD and IPF. Although these chronic lung diseases differ in their geoepidemiology and immunopathogenesis, emerging evidence suggest that organ-specific autoimmunity may underlie subphenotypes of COPD and IPF. In particular, the links to tobacco smoking, diet, gender, and environment are explored in this review. We also highlight potential mechanisms that could guide future investigations in both laboratory and clinical settings. A paradigm shift is needed in how we think about COPD and IPF, based on geoepidemiology and a broader understanding of disease pathogenesis that may ultimately lead to new therapies and improved patient outcomes.
Subject(s)
Idiopathic Pulmonary Fibrosis/epidemiology , Pulmonary Disease, Chronic Obstructive/epidemiology , Autoimmunity , Clinical Trials as Topic , Diet , Humans , Idiopathic Pulmonary Fibrosis/immunology , Incidence , Organ Specificity , Prevalence , Pulmonary Disease, Chronic Obstructive/immunology , Risk Factors , Sex Factors , Smoking/adverse effectsABSTRACT
Post-translational sulfation of tyrosines affects the affinity and binding of at least some chemokine receptors to their ligand(s) and has been hypothesized to be a feature in all chemokine receptors. This binding initiates downstream signaling cascades. By this mechanism, tyrosine sulfation can influence the cells involved in acute and chronic events of cellular immunity. These events include leukocyte trafficking and airway inflammation important in asthma and chronic obstructive pulmonary disease (COPD). We are using computational methods to convert the poorly defined hypothesis of more widespread sulfation of chemokine receptors to more specific assessments of how closely the sequence environment of each tyrosine residue resembles the sequence environment of tyrosine residues proven to be sulfated. Thus, we provide specific and readily tested hypotheses about the tyrosine residues in all of the chemokine receptors. Tyrosine sulfation was predicted with high scores in the N-terminus domain of 13 out of 18 human chemokine receptor proteins using a position-specific scoring matrix, which was determined to be 94.2% accurate based on Receiver Operating Characteristic analysis. The remaining chemokine receptors have sites exhibiting features of tyrosine sulfation. These putative sites demonstrate clustering in a manner consistent with known tyrosine sulfation sites and conservation both within the chemokine receptor family and across mammalian species. Human chemokine receptors important in asthma and COPD, such as CXCR1, CXCR2, CXCR3, CXCR4, CCR1, CCR2, CCR3, CCR4, CCR5, and CCR8, contain at least one known or predicted tyrosine sulfation site. Recognition that tyrosine sulfation is found in most clinically relevant chemokine receptors could help the development of specific receptor-ligand antagonists to modulate events important in airway diseases.
Subject(s)
Lung Diseases/metabolism , Protein Processing, Post-Translational , Receptors, Chemokine , Sulfates/metabolism , Tyrosine/metabolism , Amino Acid Sequence , Animals , Databases, Protein , Humans , Molecular Sequence Data , Receptors, Chemokine/genetics , Receptors, Chemokine/metabolism , Sequence Alignment , Tyrosine/chemistryABSTRACT
Evidence suggests that amino terminal extensions of CCK-8 affect the carboxyl terminal bioactive region of CCK. Cat CCK-58 was purified by low pressure reverse phase and ion-exchange chromatography steps and several reverse phase HPLC steps. The purified peptide and its tryptic fragments were characterized by mass spectral analysis and microsequence analysis. The structure of cat CCK-58 is: AVQKVDGEPRAHLGALLARYIQQARKAPSGRMSVIKNLQSLDPSHRISDRDY(SO3) MGWMDF-amide. Cat and dog CCK-58 are identical except for position 40 which is serine in cat and asparagine in dog. Radioimmunoassay detected cat CCK-58 about 1/10th as well as dog CCK-58, indicating a marked effect on C-terminal immunoreactivity. Cat CCK-58 with a serine at position 40, the same residue found in pig, mouse, cow and rabbit CCK-58, can be used as a unique bioprobe for defining how amino terminal amino acids influence the structure and bioactivity of the carboxyl terminal region of CCK.
Subject(s)
Cholecystokinin/chemistry , Cholecystokinin/metabolism , Protein Interaction Mapping , Sequence Analysis, Protein , Amino Acid Sequence , Animals , Cats , Cholecystokinin/genetics , Dogs , Male , Molecular Sequence Data , Protein Structure, Tertiary/physiology , Serine/metabolismABSTRACT
Homeostasis of the immune system is achieved through refined regulation and communication between immunologically relevant receptor and their cognate ligands amongst mononuclear cells during ontogeny and day to day immune responses. An aberrance in not only the kinetics of receptor expression but also the relative diversity of expression alter these events. More importantly, improper modulation of ligand binding affinity can be a triggering event that results in autoimmunity. As one of the most common post-translational modifications, tyrosine sulfation possesses the ability to regulate mononuclear cell function at various stages of the immune response. For example, removal of sulfated tyrosine residues consistently decreases the binding affinity of the ligand to its corresponding receptor as exemplified by studies of several tyrosine sulfated proteins such as PSGL-1, CD44v5, CCR5, and CXCR4, all known to play a role in a variety of autoimmune diseases. This review defines possible roles that tyrosine sulfated proteins may play in the pathogenesis of autoimmune diseases.
Subject(s)
Autoimmune Diseases/etiology , Autoimmune Diseases/metabolism , Sulfuric Acid Esters/metabolism , Tyrosine/metabolism , Animals , HumansABSTRACT
Post-translational modification of proteins by tyrosine sulfation enhances the affinity of extracellular ligand-receptor interactions important in the immune response and other biological processes in animals. For example, sulfated tyrosines in polyomavirus and varicella-zoster virus may help modulate host cell recognition and facilitate viral attachment and entry. Using a Position-Specific-Scoring-Matrix with an accuracy of 96.43%, we analyzed the possibility of tyrosine sulfation in all 1517 animal viruses available in the Swiss-Prot database. From a total of 97,729 tyrosines, we predicted 5091 sulfated tyrosine sites from 1024 viruses. Our site predictions in hemagglutinin of influenza A, VP4 of rotavirus, and US28 of cytomegalovirus strongly suggest an important link between tyrosine sulfation and viral disease mechanisms. In each of these three viral proteins, we observed highly conserved amino acid sequences surrounding predicted sulfated tyrosine sites. Tyrosine sulfation appears to be much more common in animal viruses than is currently recognized.
Subject(s)
Capsid Proteins/chemistry , Hemagglutinins, Viral/chemistry , Influenza A virus/chemistry , Receptors, Chemokine/chemistry , Sequence Alignment/methods , Sequence Analysis, Protein/methods , Sulfates/chemistry , Tyrosine/chemistry , Viral Proteins/chemistry , Algorithms , Amino Acid Sequence , Animals , Cattle , Conserved Sequence , Ducks , Horses , Humans , Molecular Sequence Data , Sequence Homology , Species Specificity , Sus scrofaABSTRACT
Posttranslational modification by tyrosine sulfation regulates many important protein protein interactions and modulates the binding affinity and specificity of seventransmembrane peptide receptors. We developed a log-odds position-specific-scoring-matrix (PSSM) to accurately predict tyrosine sulfation using 62 tyrosine sites known to be sulfated and 421 tyrosine sites known not to be sulfated. We predict that 49 tyrosines of 32 seven-transmembrane peptide receptors are sulfated. Although we did not incorporate characteristics of confirmed sulfation sites such as clustering and conservation across species into our PSSM, our predicted sites nevertheless exhibited these characteristics. The observed conservation suggests that there are strong evolutionary pressures to preserve selected biological activity of seven-transmembrane receptors. The predicted tyrosine sulfation sites predominantly occur in the extracellular tail and extracellular loop 2, regions consistent with their association with binding pockets of the receptor.