1 / 28

Extracellular Macromolecules

Extracellular Macromolecules. Glycosaminoglycans; proteoglycans; glycoproteins; mucins Glycoprotein synthesis; plasma proteins Molecular immunology: innate immunity; inflammation Molecular immunology: adaptive (acquired) immunity

primo
Download Presentation

Extracellular Macromolecules

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Extracellular Macromolecules Glycosaminoglycans; proteoglycans; glycoproteins; mucins Glycoprotein synthesis; plasma proteins Molecular immunology: innate immunity; inflammation Molecular immunology: adaptive (acquired) immunity Fibrous proteins: keratin, collagen and elastin

  2. Extracellular Macromolecules 1. Glycosaminoglycans Proteoglycans GlycoproteinsMucins

  3. Extracellular Macromolecules macromolecule% carb. glycosaminoglycans* (GAGs) 100 proteoglycans* 90-95 glycoproteins 2-30 fibrous proteins 1-2 Examples of functions: mechanical support lubrication cushioning adhesives cell spacers selective filters * aka mucopolysaccharides, mucoproteins, respectively 1

  4. Extracellular matrix in tissues • ground substance + fibers • macromolecules between cells • ground substance molecules GAGs/proteoglycans (mostly carbohydrate) • fibers fibrous proteins: structural adhesive • especially abundantin connective tissue epithelial cells adhesionmolecules extra-cellularmatrix basallamina underlying cells 2 Adapted from Hypercell

  5. A sugar GAG structure B sugar • exist as: • independent moleculese.g., hyaluronate & heparin • parts of larger structurese.g., in proteoglycans • heteropolysaccharides repeating structure: disaccharide (AB)nABABAB… • where A is usually 1 uronic acid (hexose with C6 as COO– ) • & B is 1 glycosamine (amino sugar) derivative • unbranched • glycosidic linkage • anomeric C of 1 unit linked to hydroxyl of adjacent unit 3

  6. 4 GAG structure: repeating units GAG A sugar B sugarhyaluronate glucuronate N-acetyl glucosamine * 2 5

  7. 4 GAG structure: repeating units GAG A sugar B sugarhyaluronate glucuronate N-acetyl glucosamine chondroitin sulfate glucuronate N-Ac galactosamine 4-SO4 dermatan sulfate iduronate " heparan sulfate glucuronate glucosamine N-SO3, 6-SO4 heparin iduronate 2-SO4 " keratan sulfate galactose N-Ac glucosamine 6-SO4 *opposite configuration in iduronate glucuronate/iduronate: epimers at C5 glucose/galactose: epimers at C4 * 2 5

  8. 5 Hyaluronate (aka hyaluronan) • mol wt: 106 – 107 (5000 – 50,000 monosaccharide units) • very polar: 2 hydroxyls/unit 6 heteroatoms/unit COO– every other unit binds cations: Na+, Ca++ Display of HA in motion A B A B A B hyastk2.gif – – – 1 2 3 4 5 6 (glucuronate–N-acetyl glucosamine)3 (glcUA–glcNAc)3

  9. 6 Hyaluronate: structure & properties • extended structure (charge repulsion) • hydrophilic: binds 10–100 × wt in H2O • additional, loosely associated H2O, so that volume occupied ~1000 × weight Display of HA with glcUAs in CPK hyacpk2.gif – – – 2 3 1 4 6 5 (glcUA–glcNAc)3 glcUAs in space-filling form (CPK)

  10. Hyaluronate Alberts et al. Fig. 19-37 • solutions viscous, gel–like, compression-resistant • occurrence: EC matrix,esp. in developing tissue healing wounds synovial fluid • functions: lubricant shock absorber flexible cement attachment site path for cell migration • made by fibroblasts • degraded by hyaluronidase hyaluronidase • bacterial hyaluronidase facilitates spread of infection 7

  11. Heparin • mol wt ~ 104 • ~ 40 monosaccharide units • made & released from mast cells in lungs & liver heparin cell 8

  12. Heparin • mol wt ~ 104 • ~ 40 monosaccharide units • made & released from mast cells in lungs & liver • also associated with luminal surface of endothelium • anticoagulant • forms complex with antithrombin III • this complex binds to thrombin, inactivating it • as a result, clot growth is limited • fast-acting, making it therapeutically useful heparin cell 8

  13. Extracellular Macromolecules macromolecule% carb. glycosaminoglycans* (GAGs) 100 proteoglycans* 90-95 glycoproteins 2-30 fibrous proteins 1-2 Examples of functions: mechanical support lubrication cushioning adhesives cell spacers selective filters * aka mucopolysaccharides, mucoproteins, respectively

  14. Proteoglycans (PGs) from Alberts et al. Fig. 19-57 • composed of as many as 200 GAG chains covalently bonded to a core protein via serine side chains • molecular weight range: 105 – 107 • GAG chains: chondroitin sulfate, heparan sulfate, dermatan sulfate, keratan sulfate Examples • decorin • many connective tissues • binds type I collagen, TGF-β • perlecan • basal laminae • structural & filtering function • aggrecan • syndecan (slide 13) AlbertsT 19-3:Dcrn GAGchndSO4/drmSO4 GAG chains core protein 9

  15. PG in basal lamina of renal glomerulus adapted from Alberts et al., 3 ed., Fig. 19-56 • network offibrousproteins &perlecanPG forms filter entactin perlecan GAG:heparan SO4 laminin type IV collagen 10

  16. Proteoglycans: aggrecan • ~100 GAG chains/molecule • ~100 monosaccharides/GAG chain • each "bristle" = 1 GAG chain • each GAG chain is either chondroitin sulfate or keratan sulfate • GAG chains linked to ser side chains of core protein based onAlberts et al. Fig. 19-37 4ed. 19-40 core protein GAG chains 11

  17. An aggregate of aggrecans & hyaluronan ç 1μm è • major GAG–PGin cartilage • link proteins bind noncovalently • with bound H2O,disperses shocks,compressive force • ~ cell size • adhesion proteins link to collagen & cells • degraded by chondroitin sulfatase, etc core protein link proteins hyalur-onan keratansulfate chondroitinsulfate 12 Alberts et al. Fig. 19-41

  18. Proteoglycans: syndecan • cell-surface PG • core protein domains • intracellular • transmembrane • extracellular 5 GAGs attached • functions • interactions • cell-cell • cell-matrix • growth factor receptor GAG chains outside inside core protein Lehninger et al.Fig. 9-22 13

  19. GAG synthesis & breakdown –UDP • synthesis • activated precursors: UDP–monosaccharide derivativese.g., UDP–glucuronate • residues added one at a time in Golgi complex • sulfate moieties • donor: PAPS (active sulfate) • degradation • lysosomes • specific glycosidases & sulfatases • mucopolysaccharidoses • genetic disorders • accumulation of GAG due to absence of a specific glycosidase or sulfatase – adenine – – – 14

  20. Extracellular Macromolecules macromolecule% carb. glycosaminoglycans (GAGs) 100 proteoglycans 90-95 glycoproteins* 2-30 fibrous proteins 1-2 * polypeptide with 1 or more oligosaccharide side chains 15

  21. Glycoproteins: functions of glyco moieties Glycosylation:one kind of post-translational modificationothers: phosphorylation carboxylation • increase protein’s solubility & hydrophilicity (sl 19) • stabilize protein against • denaturation • proteolysis • markers • direct protein's destination • organelle • plasma membrane • export (secretion) • indicate protein's lifetime (sl 21) • part of the protein's receptor recognition site (sl 23) • signal factors such as hormones, cytokines • cell-cell adhesion proteins 16

  22. 17 Glycoprotein structure • polypeptide with 1 or more oligosaccharide side chains • oligosaccharide linked to polypeptide in two ways: type linked to side chain of organelle where sugars are added to protein O-linked serine (ser), threonine (thr), Golgi complex lumen (O-glycoside) hydroxylysine (in collagen) N-linked asparagine (asn) rough ER lumen (N-glycoside)

  23. Glyco moiety structure • oligosaccharide chain extends away from protein surface • units mostly hexoses in pyranose (6-atom ring) form • branched • glycosidic links varied: α or β 1,2; 1,3; 1,4 • terminal sugaroften sialate 2 asn 7 2 7 asn 18 Stryer 4ed., p. 463

  24. Mucins: salivary glycoproteins • mol wt ~ 106 • ~800 short (disaccharide) side chains • terminal sugar is sialate • anionic sugar • at end of glyco chains of many glycoproteins • very hydrophilic, extended structure ~ ~ galNAc sialate – 2 19

  25. ~ ~ ~ ~ Mucins: modification & aggregation • sialidase (neuraminidase) • catalyzes hydrolysis of sialates from mucins • secreted by oral bacteria • products: • less hydrophilic, less H2O-soluble, more folded, more aggregated • part of the enamel pellicle & dental plaque matrix ~ ~ galNAc sialate x H2O sialidase x 20

  26. Role of glyco moiety in controlling protein lifetime • many blood proteins have glyco chains with terminal sialate • endothelial surface sialidases slowly remove sialates from these circulating proteins • rate of sialate removal depends on protein's structure • now-exposed gal–glcNAc… residues bind to asialoglycoprotein receptor on liver cell surface • protein is then endocytosed & broken down sialoglycoprotein:sia–gal–glcNAc–[core sugars]–protein asialoglycoprotein:gal–glcNAc–[core sugars]–protein 21

  27. core sugars Blood group types Type O cell surface: gal–glcNAc–gal–glc–protein† |fucose* Type A cell surface:galNAc–gal–glcNAc–gal–glc–protein† |fucose • A: have – enzyme to add galNAc to core sugars– antibody to type B antigen • B: have – enzyme to add gal to core sugars– antibody to type A antigen • O: have – neither enzyme • AB: have – both enzymes (either galNAc or gal added to core sugars) Type B cell surface:gal–gal–glcNAc–gal–glc–protein† |fucose both antibodies neither antibody 22 *6-deoxygalactose †or lipid

  28. Glyco moiety-binding proteins: lectins • contain sites that bind specific glyco structures • e.g., asialoglycoprotein receptor described on sl 21 • important in intercell adhesion (i.e., lectins are CAMs: cell adhesion molecules) • selectins:plasmamembranelectins thatmediatecell-cellrecognition& adhesion Lehninger et al.Fig. 7-37 23

More Related