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BIOC12FALL2012 Lecture Week 7 Notes.docx
BIOC12FALL2012 Lecture Week 7 Notes.docx

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University of Toronto Scarborough
Biological Sciences
Rongmin Zhao

BIOC12FALL2012 Lecture Week 7: Protein Functions (Chapter 15) Myoglobin  Small intracellular protein in vertebrate muscles  only in cardiac myocytes and skeletal muscle fibres  The colour of myoglobin usually represents the colour of meat (red or purple)  Immunohistochemical localization of myoglobin in differentiated mouse C2C12 Myotubes  green= myoglobin, red= nucleus   whale sperm myoglobin  contains 153 amino acids (sperm whale myoglobin)  first protein wih known x-ray structure  human myoglobin contains 154 amino acids  contains 8 helices: A-F and short inter helices region such as CD, EF and GH   myoglobin can bind O 2  the major function of myoglobin is to facilitate oxygen diffusion in muscles  acts as oxygen storage  myoglobin is not essential for muscles under normal conditions (knockout mice are normal) Myogloin contains a Heme group  heme is a porphyrin derivative conaining 4 pyrrole groups (proline side cian is a pyrrolidine group)  heme occurs in many proteins: myoglobulins, hemoglobulin, neuroglobulin, cytochrome c etc  heme sits in a hydrophobic pocket  oxygenation alters the electronic state of the Fe2+-Heme complex and causes the colour change  Fe2+ is coordinated by His F8  ferrous ions interacts with six ligands Mb  4 of these are the N atoms of the porphyrin 1  a 5 ligand is donated by the imidazole side chain of amino acid residue His F8  this residue is on the 6 th th or F helix and it is the 8 residue in the helix, hence its name  when myoglobin binds oxygen, then O2 molecule adds to the heme iron as the sixth ligand  the O2 molecule is tilted relative to a perpendicular to the heme plane   the heme is tightly held in the myoglobin molecule  Val E11 and Phe CD1 help to hold the heme in place O 2inding Alters Mb Conformation  In deoxymyoglobin, the ferrous ion actually lies o.55A above the plane of the heme  When oxygen binds to Fe in heme of Mb, the heme Fe is drawn toward the plane of the porphyrn ring  With oxygen bound, the Fe2+ atom is only 0.26A above the plane  For Mb, this small change has little consequence Oxygen binding property Mb+O 2MbO 2 Dissociation constant: [Mb][O2] [Mb][O 2 k = Þ[MbO ]2 (1) [MbO 2 k The dissociation constant is often ed ressed as k Fractional saturation: defined as the fr2ction of O -binding site occupied by O2 [MbO ] YO2 = 2 (2) [Mb]+[MbO ] 2 Substitute [2bO ] in (2) by the formula (1): [O ] Y = 2 O2 k +[O ] 2   since O2 is a gas, [O2] is usually expressed as the partial pressure (oxygen tension), pO2  Therefore: Oxygen Binding Curve of Myoglobin 2   this function is a rectangular hyperbola  k is the value of pO2 at 50% MbO2 saturation  1 atm = 760 torr = 760 mmHg Hemoglobin  hemoglobin is a tetramer   hemoglobin alpha and beta and human myoglobin share very high similarity of amino acids  hemoglobin is located in red blood cells  structurally (homologue) related to myoglobin  but only 18% of residues are identical in myoglobin and in the alpha and beta subuntis of hemoglobin  functions for O2 transport  Hb has an α β tetrameric structure 2 2  Figure above: an ab dimer of Hb, with packing contacts indicated in blue  the sliding contacts made with the other dimer are shown in yellow  Hemoglobin is in an exact C2 symmetry structure  protomer αβ  Hemoglobin is in a pseudo-D2 symmetry  becase the alpha and beta subunits are not exactly the same  Hemoglobin binds O2 showing a sigmoidal binding curve   sigmoidal curve – S shaped  comparing the hyperbola curve: at low pO2, lower binding and at high pO2, higher binding for sigmoidal mode  sigmoidal binding curve always shows a cooperative binding  binding of one ligand affects the other ligand binding sites  hyperbola binding curve always shows an independent binding  binding of one ligand does not affect the other ligand binding sites An Alternative O2-Binding curver for Hb 3  oxygen saturation curve for Hb in the form of Y vs. pO2 assuming n=4 and P50 =26 torr  Y is the fractional saturation of Hb    a comparison of the experimentally observed O2 curve (blue) for Hb yielding a value for n of 2.8, the hypothetical curve if n=4 in pink, and the curve if n=1 (non interacting O2- binding sites) in grey  The Conformation Change  the secret of Mb and Hb  oxygen binding changes the Mb conformation  without oxygen
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