• Introduction to Protein Structure and Function
• 40 min
  1. Nature’s strategies in the regulation of enzyme activity by modifiers

  • Prof. Antonio Baici
• Creation of Protein Variability by Manipulation of Genes
• 28 min
  2. Understanding protein variability through functional analysis of random mutagenesis

  • Prof. Andrew Kaplan
• 48 min
  3. Perspectives on biological catalysis

  • Prof. Stephen Benkovic
• 45 min
  4. Fundamentals and principles for engineering proteolytic activity

  • Prof. Charles Craik
• Metabolic Diseases Caused by Genetic Mutation
• 36 min
  5. Modifications of pyruvate handling in health and disease

  • Prof. Mary Sugden
• 29 min
  6. Mitochondrial fatty acid oxidation deficiencies

  • Prof. Niels Gregersen
• 33 min
  7. Inborn errors of ketone body metabolism

  • Prof. Toshiyuki Fukao
• 34 min
  8. Cathepsin K in bone and joint diseases

  • Prof. Dieter Bromme
• 22 min
  9. Fabry disease: alfa-galactosidase A deficiency and enzyme replacement therapy

  • Prof. David Warnock
• 47 min
  10. Acid beta-glucosidase/glucocerebrosidase (GCase)

  • Prof. Gregory Grabowski
• 23 min
  11. GM2 gangliosidosis future treatments 1

  • Prof. Brian Mark
• 19 min
  12. GM2 gangliosidosis future treatments 2

  • Prof. Brian Mark
• 29 min
  13. The neuronal ceroid lipofuscinoses

  • Prof. Sandra Hofmann
• Disorders of Blood Coagulation
• 24 min
  14. Advances in fibrinolysis

  • Dr. Paul Kim
• 26 min
  15. Tissue factor and factor VII: initiation of blood coagulation

  • Dr. John McVey
• 36 min
  16. Structure of thrombin, a Janus-headed proteinase

  • Prof. Wolfram Bode
• 45 min
  17. The protein c-thrombomodulin mechanism: regulating multiple biological systems

  • Prof. Edward Conway
• 40 min
  18. Fibrinogen and factor XIII

  • Prof. John Weisel
• 31 min
  19. Factor VIII and haemophilia A

  • Dr. Geoffrey Kemball-Cook
• 34 min
  20. Factor IX

  • Prof. Bruce Furie
• 42 min
  21. The biology and pathobiology of von Willebrand factor

  • Prof. David Lillicrap
• 40 min
  22. Thrombotic thrombocytopenic purpura

  • Prof. J. Evan Sadler
• 26 min
  23. Fibrinolysis

  • Prof. Edward Tuddenham
• Other Molecular and Metabolic Disorders
• 45 min
  24. Glucose-6-phosphate dehydrogenase deficiency

  • Dr. Jane Leopold
• 26 min
  25. Cytochrome b5 reductase deficiency and hereditary methemoglobinemia

  • Dr. Scott Reading
• 50 min
  26. Sickle cell disease

  • Prof. Martin H. Steinberg
• 40 min
  27. Pyruvate kinase deficiency

  • Prof. Alberto Zanella
• 47 min
  28. Heritable disorders of collagen

  • Dr. Heather Yeowell
• 40 min
  29. Duchenne muscular dystrophy

  • Prof. Jeff Chamberlain
• Archived Lectures *These may not cover the latest advances in the field
• 33 min
  30. Protein crystallography

  • Prof. Michael James
• 48 min
  31. Regulation of blood coagulation by the serpin, antithrombin

  • Prof. Steve Olson
• 37 min
  32. Rhodopsin and retinitis pigmentosa

  • Dr. Shalesh Kaushal
• 40 min
  33. The physiology and pathology of coagulation factor XI

  • Dr. David Gailani
• 24 min
  34. Cytochrome b5 reductase deficiency and hereditary methemoglobinemia

  • Prof. Josef Prchal
• 49 min
  35. Metachromatic leukodystrophy

  • Prof. Volkmar Gieselmann
• 21 min
  36. Serpins and serpinopathies

  • Dr. James Whisstock
• 27 min
  37. Multiple acyl-CoA dehydrogenation deficiency: defects of electron transfer flavoproteins

  • Dr. Rikke Olsen
• 39 min
  38. Pleiotropic and epistatic genes in sickle cell anaemia

  • Prof. Ronald Nagel
• 44 min
  39. Genetic disorders of carbonic anhydrases II and IV

  • Prof. William Sly
• 39 min
  40. GM2 gangliosidoses

  • Prof. Don Mahuran
• 48 min
  41. Kinetic analysis of protein activity

  • Prof. Antonio Baici

Printable Handouts

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Navigable Slide Index

1. Introduction
2. The carbonic anhydrase (CA) reaction
3. The first known inherited CA deficiency syndrome
4. First feature: bone fracture and osteopetrosis
5. The reasons for suspecting it was a new disease
6. Second feature: renal tubular acidosis (RTA)
7. Third feature: cerebral calcification
8. What enzyme deficiency produce such defects?
9. Patterns of erythrocyte CA I and CA II
10. My first paper on carbonic anhydrases
11. Osteopetrosis/RTA always true for CA II-deficiency
12. 16 structural gene mutations in CA II-deficiency
13. The proposed roles of CA II and CA IV
14. How do we explain cerebral calcification?
15. 1983: 50-year anniversary symposium
16. How was carbonic anhydrase discovered?
17. Purified enzyme was found to contain zinc
18. 1945 - 1960: the middle years
19. 1960 - 1980: the protein era
20. Other CA family members known by 1983
21. Why six enzymes for such a simple reaction?
22. Partial answer: compartmentalization
23. 260-amino acid CA domain is common to all CAs
24. N-terminal a.a sequences of catalytic human CAs
25. C-terminal a.a sequences of catalytic human CAs
26. CA-related proteins (CARPs)
27. Why was CA IV of special interest?
28. CA IV in the lumen of the proximal renal tubules
29. Immunofluorescent labeling of CA IV
30. Cartoon of the CA IV-membrane interaction
31. Back to the American family with CA II-deficiency
32. What CA IV does in your proximal tubules
33. How to prove it? find a CA IV deficient patient
34. On to the mouse!
35. Mouse knockout has no kidney phenotype
36. CA IV and CA XIV in kidney proximal tubules
37. Wrong predicted CA IV deficiency phenotype
38. Summary of CA IV and CA XIV findings in kidney
39. Confocal laser scanning images of CA XIV
40. CA XIV enrichment in specific membrane domains
41. CA XIV is the membrane CA in the retina
42. CA IV and XIV knockout mice
43. We thought we were finished with CA IV...
44. South African family with retinitis pigmentosa
45. What is retinitis pigmentosa (RP)?
46. What does the retina look like in RP?
47. Rhodopsin mutations and retinal disorders
48. Predicted R14W mutation effect on CA IV protein
49. Could we find a precedent?
50. CA IV is absent in the retina
51. CA IV is highly expressed in the choriocapillaris
52. A working hypothesis for RP17
53. What is the UPR?
54. How does the UPR help the cell handle ER stress
55. R14W mutant CA expression in COS-7 cells
56. R14W mutation reduces-steady state level
57. Turnover of R14W and wild-type CA IV protein
58. R14W mutation and induction of ER proteins
59. R14W CA IV-induced ER stress and apoptosis
60. R14W CA IV induces upregulation of CHOP
61. R14W CA IV induces Annexin V / TUNEL staining
62. Apoptosis-inducing signal sequence in CA IV
63. So what? good question!
64. If RP17 is a protein folding disease...
65. Acetazolamide and R14W CA IV degradation rate
66. PBA and R14W CA IV biosynthesis and stability
67. Will CA inhibitors reduce UPR gene upregulation?
68. Chemical chaperones and apoptosis protection
69. Summary
70. Future studies
71. Immunofluorescence of transgenic retina
72. TUNEL staining of retina from control mouse
73. R14W CA IV transgenic mouse retina staining

Topics Covered

• Carbonic anhydrase deficiencies
• History of the disease
• Roles of CA II and IV in disease
• Sulfonamide inhibitors for treatment of some disorders
• Characterization of CA isozymes
• CA IV discovery and function
• Mouse knockout models of CA deficiencies
• CA IV, unfolded protein response and retinitis pigmentosa
• ER stress and apoptosis in the choriocapillaris
• Chemical chaperones and treatment of retinitis pigmentosa
• Future studies

Links

Series:

• Protein Epidemiology

Categories:

• Biochemistry
• Cell Biology
• Clinical Practice
• Genetics & Epigenetics

Therapeutic Areas:

• Gastroenterology & Nephrology

Talk Citation

Publication History

• Published on October 1, 2007
• Archived on February 25, 2021

Financial Disclosures

• Prof. William Sly has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.