Highly Asymmetric Interactions between Globin Chains in the Hemoglobin Assembly Process as Revealed by Electrospray Ionization Mass Spectrometry
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1 Highly Asymmetric Interactions between Globin Chains in the Hemoglobin Assembly Process as Revealed by Electrospray Ionization Mass Spectrometry Wendell P. Griffith, and Igor A. Kaltashov Department of Chemistry, University of Massachusetts, Amherst, MA 01003
2 Overview In vitro assembly of hemoglobin (Hb) by monitoring the assembly/dissociation equilibria under a variety of solution conditions using electrospray ionization mass spectrometry and circular dichroism spectrophotometry. The experimental data provide strong evidence that binding of a partially unstructured apo-β-chain to a tightly folded holo-α-chain to form a heme-deficient dimer is the initial step of hemoglobin assembly. Such binding locks the β-chain in a highly ordered conformation, which allows for an efficient heme acquisition, followed by the docking of two dimers to form a tetrameric form of the protein.
3 Introduction Why study hemoglobin assembly/dissociation? The majority of research efforts have been geared towards the characterization of ligand-binding properties. The dissociation of the hemoglobin molecule has a direct effect on its oxygen-binding properties. Hemoglobin scavengers like haptoglobin do not bind to the intact protein, thus Hb dissociation is an important determinant of its rapid clearing from circulation during hemolysis or following the transfusion of Hb-based oxygen carriers. Numerous devastating disorders like thalassemia and sickle-cell anemia have been linked to abnormalities in the hemoglobin dissociation process.
4 Hemoglobin Assembly in vivo Luzzatto and Notaro, Nature 2002, 417, 703
5 Possible Dynamic Solution Equilibria #1. α* + β* α*β* generally assumed #2. α* + β α* β α*β + heme α*β* #3. α + β αβ αβ + heme α*β*
6 Experimental Mass Spectrometry: JMS-700 MStation (JEOL, Tokyo, Japan) two-sector instrument with standard ESI source Circular Dichroism: JASCO J-715 CD spectropolarimeter (Jasco Corp., Tokyo, Japan) Materials: bovine hemoglobin (PDB# 1G0A), horse heart myoglobin (PDB# 1AZI)
7 Mass spectrum for Hemoglobin at near physiological ph +18 (α*β) +12 (α*β) +13 (α*β*) +12 β (α*) +8 (α*) +7
8 Take-Home Messages: Prominent contributions to ion signal from tetrameric and dimeric species Heme-deficient dimer Partially unstructured apo-β-globin Tightly folded holo-α-globin No holo-β-globin or apo-α-globin present
9 + Solution ph ph 3 ph 4 ph 5 ph 8
10 Circular Dichroism Soret band 2 structure heme-binding
11 Data Analysis MS MS % Folded Protein CD (222 nm) % Heme-bound Protein CD (Soret) due to deprotonation of some non-coordinating aromatic residues in heme-binding pocket ph ph
12 myoglobin α-globin β-globin ph 8 ph 4
13 Pathway concluded by Experiment + α* N + β U (α*β) N (α*β*) N ()N
14 Chain Isolation from Apo-bovHb Intens. [mau] M expt : M calc : M expt : M calc : Alpha globin Beta globin Time [min]
15 Comparison with Isolated Chains (α*) +8 (α*β) +13 (α*β*) (α*) +9 β +16 β +9 β +8 (β*) +8 (β*β*) +12
16 Conclusions There is a surprising asymmetry in the roles played by α- and β-globins in hemoglobin assembly. α-globin provides a rigid template for assembly. β-globin is very flexible (intrinsically disordered) for the efficient accommodation of the α-globin. The β-globin s structure is locked and its flexibility diminished once the α*-β binding has occurred. α*β is an important intermediate in the hemoglobin assembly/dissociation pathway. Asymmetry is important for correct binding in the crowded environment of the red blood cell.
17 References Perutz, M. (1997) Science is not a quiet life: Unravelling the atomic mechanism of haemoglobin, World Scientific Publishing Co. Pte. Ltd., Singapore. Vasudevan, G., and McDonald, M. J. (2002) Curr. Protein Pept. Sci. 3, Acknowledgements Stephen J. Eyles, Mass Spectrometry center at the University of Massachusetts, Amherst NIH R01 GM61666
18 Afterthoughts All of the conclusions of this study are based on the assumption that there is a non-occurrence of gas-phase dissociation of the Hb non-covalent complex. Addenda A and B show some of the results of experiments carried out to investigate the effects of ESI source parameters on complex dissociation. Note the asymmetric dissociation of the Hb tetramers to form trimers and complementary monomers at high orifice potentials. These trimer ions are absent from the spectrum acquired under mild source conditions. Hb tetramer ions do not dissociate in the gas phase under conditions used in this work.
19 Addendum A Gas phase dissociation - the effect of increasing the orifice 1 potential 100 (α*) +8 x heme β +16 β +16 (a*) +11 heme β +17 (α*) +11 heme (α*) +9 (α*β*) +12 (α*) +9 (α*) +8 (α*) +7 (α*) +7 O O O (α*) +6 O O +12 (α*β*) (α*) +8 (α*) +7 (α*) +6 (α*) +9 (α*β*) +12 (α*) +8 (α*)+9 (α*) +7 α +8 (α*) +10 α +7 O O O O β (α*) (α*) +6 α +6 α (α*) V 30 V 60 V 130 V heme α +7 α +8 α +6 α +9 (α*) +7 α +5 β +6 β +5 α V
20 Addendum B Gas phase dissociation in high m/z region - the effect of increasing the orifice 1 potential α +4 (α ) +4 β +4 (α 2 β ) +12 (β ) +4 (α β ) +10 or (αββ ) +10 (α β ) +11 or (αββ ) (α β ) +10 (α β ) (αβ ) +10 or (α ββ ) (αβ ) +11 or (α ββ ) (α β ) (α β α +3 ) V V V V 195 V
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