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Ch. 7 Protein Function and Evolution

Ch. 7 Protein Function and Evolution. Myoglobin and Hemoglobin. Both are essential for oxygen need Myoglobin stores O 2 in the muscle Hemoglobin transports O 2 to tissues and CO 2 and H + back to lungs

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Ch. 7 Protein Function and Evolution

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  1. Ch. 7 Protein Function and Evolution

  2. Myoglobin and Hemoglobin • Both are essential for oxygen need • Myoglobin stores O2 in the muscle • Hemoglobin transports O2 to tissues and CO2 and H+ back to lungs • The 2o structure of hemoglobin resembles myoglobin but the 4o structure allows for interactions that are central to its function.

  3. Structure • Figure 7.3 page 214 • Notice Hemoglobin appears to be constructed of 4 Myoglobin strands • Figure 7.4 page 215 • Heme is composed of 4 pyrrole rings linked by a-methylene bridges. • As a whole, the molecule is called Porphin • Each Porphin binds 1 Ferrous Ion (Fe2+)

  4. Structure, cont. • Oxidation of the iron to Fe3+ destroys biological function

  5. Myoglobin • Oxygen stored is released to prevent oxygen deprivation • The oxygen goes to the mitochondria for synthesis of ATP • Myoglobin is composed of about 75% alpha helixes which is unusually high • As with most globular proteins, outside is polar and inside is non-polar

  6. His at E7 and F8 • The eight helixes are termed A-H starting at the amino terminal • Notice the Histidine residues at E7 and F8, near the site of Heme (porphin system) Figure 7.5 page 216 • His contains pyrrole like ring as a side chain • Heme binds to myoglobin with the propanate groups towards the outside (polar) and the nonpolar methyl and vinyl groups towards the inside (see fig 7.4c)

  7. Histidines • The F8 His actually provides a fifth coordination to the iron providing an actual linkage to the protein. (fig 7.5b) • The other histidine, E7, lies on the opposite side. (more on this later!) • Due to the coordination to the F8 His, the iron lies outside the plane of the heme and puckers the heme slightly

  8. Heme binding of O2 • When the iron binds O2, the iron moves closer to the plane, pulling the F8 His with it, thus slightly altering the other residues near the F8 His. • When the O2 binds, the preferred orientation is with the O-Fe-Heme bond at 90o and the Fe-O-O bond at 121o

  9. Heme binding to CO • The iron actually binds CO with a similar bond that is 25,000 times stronger! • However, the C of the CO is sp hybridized and so the Fe-C-O bond should be 180o • This angle is not allowed due to the presence of the E7 Histidine. • There is a lone pair of electrons on the Nitrogen that creates steric and electronic repulsions

  10. Heme binding to CO • As a result, CO is forced to bond like O2 and the C-O-Fe bond is significantly weakened. • This weakening allows for the great abundance of O2 to predominately bind.

  11. Myoglobin: Storage vs. Transport • Myoglobin is better for storage than transport • The reasoning is seen in the Oxygen binding curve. (fig 7.6, page 217) • Notice how the % saturation doesn’t begin to drop until the PO2 is very low. • This means that Myoglobin would not release O2 in normal conditions, only in very low levels of O2

  12. Hemoglobin • The additional properties of hemoglobin that allow it to effectively transport O2 arise from it 4o structure. • These are referred to as allosteric properties, meaning “other space” • Hemoglobin is tetrameric and contains 2 pairs of different peptide sub units • The 1o structure of b,g,d are highly conserved

  13. Comparisons • Myoglobin and b-subunits have almost identical 2o and 3o structures • The a strand is also similar but only contains 7 helices rather than 8

  14. Hemoglobin • Hemoglobin contains 4 heme groups, therefore it can bind 4 O2 molecules per 1 hemoglobin • Recall that the binding of O2 slightly changes the structure of the heme and connecting protein • This slight change allows for the next O2 to bind easier

  15. This is called cooperative binding • Cooperative binding helps hemoglobin both load and unload O2 • Cooperative binding is only seen in multimeric proteins.

  16. P50 • P50 is the quantity used to express O2 partial pressure • P50 is the partial pressure of O2 that half saturates a given hemoglobin • P50 will vary organism to organism but will always exceed the PO2 in peripheral tissues

  17. Cooperative Binding • The reason hemoglobin experiences cooperative binding is the large conformational changes that hemoglobin undergoes when O2 is bound • When O2 in bound, one of the a/b subunits rotates 15o creating a more complex structure • The relates to profound changes in the 2o, 3o, and 4o structure

  18. Conformations • Hemoglobin with no O2 bound is said to be in the T (taut) form. (Fig 7.13, page 225) • Once O2 is bound, the hemoglobin shifts to the R (relaxed) form. • This conformational shift is what lowers the binding energy for the remaining O2 to bind • Less conformational change is needed.

  19. The Return Trip • Hemoglobin not only transports O2 from the lungs to peripheral tissues, but also transports CO2 and H+ from the peripheral tissues back to the lungs • The CO2 is the by-product of respiration in cells • The CO2 does not bind to the same sites as O2.

  20. Transport of CO2 • CO2 forms carbamates with terminal amino groups of the proteins of Hemoglobin • This binding of CO2 changes the charge at the N-terminal from + to – • This favors additional salt bridges holding hemoglobin together.

  21. Transport of CO2 • Only about 15% of CO2 in transported in this manner • Most of the rest is transported as bicarbonate • Bicarbonate is formed in erthrocytes by the hydration of CO2 which is catalyzed by carbonic anhydrase • Initially, carbonic acid is formed but immediately deprotonates at the pH of the blood

  22. Acidic Environment • Hemoglobin will bind one H+ for every 2 O2’s released • This plays a major role in buffering capacity of blood • The delivery of O2 is enhanced by the acidic environment of the peripheral tissues due to the carbamation stabilizing the T form.

  23. In Lungs • In the lungs the whole process is reversed! • The reciprocal coupling of H+ and O2 binding is termed the Bohr effect.

  24. Bohr Effect • The Bohr Effect is dependent upon the cooperative interactions between the hemes of the tetramer • Therefore, Myoglobin would not show the Bohr Effect • So, where do the protons in the Bohr Effect come from and how do they help enhance the release of O2?

  25. You had to ask!!!!

  26. Other Factors • Release of O2 is also enhanced by the presence of 2,3-biphosphoglycerate (BPG) • BPG is synthesized in erythrocytes at the low O2 concentrations at peripheral tissues • BPG helps stabilize the T form of hemoglobin • It binds in the central cavity formed by the four subunits of hemoglobin (Fig 7.18 p 229) • Only the T form binds BPG

  27. The space between the H helices of the b chains that line the cavity sufficiently opens only in the T form • BPG forms salt bridges with the positive charges on the terminal amino groups of both b chains via NA1 (1) and with Lys EF6(82) and His H21 (143). • These salt bridges must be broken to return to the R state.

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