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MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY Glycoprotein Hormones

MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY Glycoprotein Hormones. 1. The glycoprotein hormones - main actions 2 Structure; subunits 3. Glycosylation 4. Biochemical mode of action 5. Clinical aspects. Thyrotropin (TSH) (thyroid stimulating hormone). glycoprotein (2 subunits).

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MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY Glycoprotein Hormones

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  1. MOLECULAR ENDOCRINOLOGY AND IMMUNOLOGY Glycoprotein Hormones 1. The glycoprotein hormones - main actions 2 Structure; subunits 3. Glycosylation 4. Biochemical mode of action 5. Clinical aspects

  2. Thyrotropin (TSH) (thyroid stimulating hormone) glycoprotein (2 subunits) stimulates thyroid hormone production Follicle stimulating hormone (FSH) (follitropin) glycoprotein (2 subunits) stimulates maturation of Graffian follicle (female) and spermatogenesis (male) Luteinizing hormone (LH) (lutropin, interstitial cell stimulating hormone) glycoprotein (2 subunits) stimulates ovulation and development of corpus luteum (female), steroidogenesis (male) Human chorionic gonadotropin (hCG) glycoprotein (2 subunits) Maintenance of corpus luteum Glycoprotein Hormones

  3. hCG showing seat belt

  4. hCG showing cystine knots

  5. Structures proposed for oligosaccharide moieties of hCG (a) N-linked oligosaccharides, (b) O-linked oligosaccharides. NeuNAc, N-acetyl neuraminic acid; Gal, galactose, GlcNAc, N-acetyl glucosamine; Man, mannose; Fuc, fucose; GalNAc, N-acetylgalactosamine

  6. Dolichol phosphate-oligosaccharide intermediate

  7. Possible function of carbohydrate moieties 1. Induce conformation necessary for a and b subunit association 2. Protection from intracellular and/or extracellular degradation 3. Required for intrinsic activity 4. Required for intracellular targeting and secretion

  8. Model of TSH receptor Indicating sites where mutation can lead to constitutive activation

  9. TSH Receptor and disease 1. Development of autoantibodies to TSH receptor can lead to over stimulation (Graves disease) or reduced stimulation (Hashimoto’s disease) 2. Receptor mutations can give loss of function or gain of function* (constitutive activation). 3. Gs protein mutations can lead to constitutive activation* * can be somatic or germ line mutations

  10. Postulated model for the LH/hCG receptor Extracellular Cytoplasmic

  11. Postulated topology of the LH receptor in the plasma membrane

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