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Lecture 6 O-GalNac Glycans C-type Lectins

Lecture 6 O-GalNac Glycans C-type Lectins. The Glycome is Rich. Man. Yeast mannoproteins a -dystroglycan. Nuclear Proteins Cytoplasmic Proteins. GalNAc. Fuc. GlcNAc. Ser/Thr. Ser/Thr. Ser/Thr. Ser/Thr. Mucins. Notch Coagulation Factors Fibrinolytic Factors. Examples of O-Glycans.

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Lecture 6 O-GalNac Glycans C-type Lectins

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  1. Lecture 6O-GalNac GlycansC-type Lectins

  2. The Glycome is Rich

  3. Man Yeast mannoproteins a-dystroglycan Nuclear Proteins Cytoplasmic Proteins GalNAc Fuc GlcNAc Ser/Thr Ser/Thr Ser/Thr Ser/Thr Mucins Notch Coagulation Factors Fibrinolytic Factors Examples of O-Glycans

  4. Glc Xyl Man Glc Gal GlcNAc Ser Ser Thr Rho proteins Worm Collagens Dictyostelium proteins Proteoglycans (Glycosaminglycans) More O-glycans

  5. Gal Glc Ara Gal GlcNAc HydroxyLys HydroxyPro Tyr Collagen C1q complement Plant glycoproteins Dictyostelium Glycogenin Even more….

  6. O H O H H O N A c H C 2 N H 2 O-Glycosidic Linkage O-glycosidic linkage is sensitive to alkali (regardless of stereochemistry) b-elimination GalNAc H O H H H a H O C C H Ser O :OH

  7. Ribbon drawing of the ppGaNTase-T1 crystal structure Fritz, Timothy A. et al. (2004) Proc. Natl. Acad. Sci. USA 101, 15307-15312

  8. Modeled binding of a MUC1 glycopeptide to ppGaNTase-T1 Fritz, Timothy A. et al. (2004) Proc. Natl. Acad. Sci. USA 101, 15307-15312

  9. Core 1 Core 2 Core 3 Core 4 b3 b6 Ser/Thr Core 6? Core 7 Core 8 Core 5 b6 a6 a3 b3 a3 b3 b3 b6 Ser/Thr Ser/Thr Ser/Thr Ser/Thr Ser/Thr Ser/Thr Ser/Thr Other Core O-Glycan Structures

  10. ST6GalNAc III, IV, I, II a3 b3 a6 b3 disialyl T-antigen ST3Gal-I, II, IV b3GalT b6GlcNAcT b3 b3 b6 Ser/Thr Ser/Thr Ser/Thr Tn-antigen T-antigen Core 2 ST6GalNAc-II, I ST6GalNAc-I a6 b3 a6 sialyl Tn-antigen sialyl T-antigen

  11. b3GalT Ser/Thr b3 Ser/Thr Cosmc • Tn-antigens accumulate due to loss of b3Gal transferase activity • No mutations in b3GalT; message is expressed • Missing Cosmc (Core 1 b3GalT -specific molecular chaperone, Xq23 • 25% identity, >40% homology to b3GalT • Absence of Cosmc results in proteosome degradation of b3GalT Cosmc Tn-antigen T-antigen Ju & Cummings (2002) PNAS 99:16613-8

  12. Is Cosmc a Chaperone? T-synthase + Mut Cosmc T-synthase + Wt Cosmc His-tagged Cosmc HPC4 tagged T-synthase Ni+ purification, Western with mAb to HPC4 T-synthase Total Bound to Ni+ Not bound to Ni+

  13. a3 b4 a3 b3 b4 b3 b4 a3 b3 b6 Outer Chain Assembly • Sequential action of b4GalT and b3GlcNAcT gives rise to polylactosamine chains (Type II repeats) • Type I repeats (Galb3GlcNAcb3) also occur • GlcNAcb6Gal branches (I-antigen) can occur • The ends of the chains are capped in a-linked sugars, e.g. a3/4Fuc and a3/6sialic acids • Terminal structures make up important blood group determinants, e.g. the Lewis antigens a Ser/Thr

  14. Intestinal Epithelium stained with Periodic acid-Schiff’s Reagent

  15. Mucins • 11p15 family (MUC2, MUC5AC, MUC5B, MUC6) probably responsible for the formation of mucus layers • 7q22 family (MUC3A, MUC3B, MUC12), 1q21 (MUC1), and 3q (MUC4, MUC13) are membrane mucins • Mucin families are not necessairly related to each other, convergent evolution Dekker et al. (2002) TIBS 27:126

  16. C-type Lectins

  17. Leukocyte Rolling Tim Springer, Harvard

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