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Understanding Animal Prion Diseases and the Structure-Function Relationship of Hemoglobin and Myoglobin

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fidelio-langan
22 diapositives · 381 Views · Nov 16, 2014

This chapter delves into the complexities of animal prion diseases such as Scrapie in sheep, Chronic Wasting Disease in mule deer and elk, and Bovine Spongiform Encephalopathy in cows, alongside their implications for human diseases like Creutzfeldt-Jakob Disease and Fatal Familial Insomnia. It also covers the essential structural and functional characteristics of myoglobin and hemoglobin, highlighting their roles as oxygen carriers. The chapter explains oxygen binding mechanisms, the impact of allosteric modulators, and the significant effects of mutations in globin genes, providing a comprehensive overview of these vital biochemical components.

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  1. Chapter 4 (part 3) 3-D Structure / Function

  2. Animal Scrapie: sheep TME (transmissible mink encephalopathy): mink CWD (chronic wasting disease): muledeer, elk BSE (bovine spongiform encephalopathy): cows Human CJD: Creutzfeld-Jacob Disease FFI: Fatal familial Insomnia Kuru

  3. Susan W. Liebman, and James A. Mastrianni (2005) Trends in Molecular Medicine 11: 439-441

  4. Myoglobin/Hemoglobin • First protein structures determined • Oxygen carriers • Hemoglobin transport O2 from lungs to tissues • Myoglobin O2 storage protein

  5. Mb and Hb subunits structurally similar • 8 alpha-helices • Contain heme group • Mb monomeric protein • Hb heterotetramer (a2b2) myoglobin hemoglobin

  6. Heme group • Heme = Fe++ bound to tertapyrrole ring (protoporphyrin IX complex) • Heme non-covalently bound to globin proteins through His residue • O2 binds non-covalently to heme Fe++, stabilized through H-bonding with another His residue • Heme group in hydrophobic crevice of globin protein

  7. Oxygen Binding Curves • Mb has hyberbolic O2 binding curve • Mb binds O2 tightly. Releases at very low pO2 • Hb has sigmoidal O2 binding curve • Hb high affinity for O2 at high pO2 (lungs) • Hb low affinity for O2 at low pO2 (tissues)

  8. Oxygen Binding Curve

  9. Oxygen Binding Curve

  10. O2 Binding to Hb shows positive cooperativity • Hb binds four O2 molecules • O2 affinity increases as each O2 molecule binds • Increased affinity due to conformation change • Deoxygenated form = T (tense) form = low affinity • Oxygenated form = R (relaxed) form = high affinity

  11. O2 Binding to Hb shows positive cooperativity

  12. T-conformation R-conformation O2 Binding induces conformation change Show Movie Heme moves 0.34 nm Exposing crystal of deoxy-form to air cause crystal to crack

  13. Allosteric Interactions • Allosteric interaction occur when specific molecules bind a protein and modulates activity • Allosteric modulators or allosteric effectors • Bind reversibly to site separate from functional binding or active site • Modulation of activity occurs through change in protein conformation • 2,3 bisphosphoglycerate (BPG), CO2 and protons are allosteric effectors of Hb binding of O2

  14. Bohr Effect • Increased CO2 leads to decreased pH CO2+ H2O <-> HCO3-+ H+ • At decreased pH several key AA’s protonated, causes Hb to take on T-conformation (low affinty) • In R-form same AA’s deprotonated, form charge charge interactions with positive groups, stabilize R-conformation (High affinity) • HCO3- combines with N-terminal alpha-amino group to form carbamate group. --N3H+ + HCO3- --NHCOO- • Carbamation stabilizes T-conformation

  15. Bisphosphoglycerate (BPG) • BPG involved acclimation to high altitude • Binding of BPG to Hb causes low O2 affinity • BPG binds in the cavity between beta-Hb subunits • Stabilizes T-conformation • Feta Hb (a2g2) has low affinity for BPG, allows fetus to compete for O2 with mother’s Hb (a2b2) in placenta.

  16. Mutations in a- or b-globin genes can cause disease state • Sickle cell anemia – E6 to V6 • Causes V6 to bind to hydrophobic pocket in deoxy-Hb • Polymerizes to form long filaments • Cause sickling of cells • Sickle cell trait offers advantage against malaria • Fragile sickle cells can not support parasite