Transcript Hemoglobin Hb : Function, Structure and Relevance to daily

Hemoglobin Hb : Function, Structure and
Relevance to daily life.
By Arwa Almejbel
CHE442:Proteins
Dr.Jon Friesen
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Introduction
• First studied in the 1800’s.
• Found in bacteria
,eukaryotic organisms and
archea.
• The heme part is
synthesized in mitochondria
and cytosol. While the
globin protein parts are
synthesized by ribosomes in
the cytosol.
• Function: to transport the
oxygen and maintain the
round shape of the RBCs.
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Hemoglobin A Structure
α1
β2
Heme
β1
α2
Red is Heme , gray is α chain and blue is β
chain. PDB ID: 1HGA
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Amino acid sequence Alignment
Glu6
Val60 His63
Gly26
Phe44
His9 Lys95
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Tyr145
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Key amino acids in Hemoglobin
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PDB ID: 1HGA
His143 (brown), Lys82(orange), and
His2(brown), interact with 2,3-BPG in
the center of the tetramer holding
the deoxyhemoglobin form in place
(salt bridges).
His63, His92 (brown) are important
for hemoglobin binding oxygen.
Phe44(green),Tyr142 (purple)stabilize
the structure by forming hydrogen
bonds between helices.
Glu6(blue) is an important in
mutagenesis studies.
Gly26 (yellow)is very small which
allows 2 helices to approach each
other.
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Oxygen binding
• Cooperative binding
• Binding to the 1st O2
facilitates the binding of
2nd ,3rd and 4th O2.
• Binding to O2 causes
conformational
changes.
PDB ID: 1hho
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The T and R transition
1 Image: http://jr.stryker.tripod.com/hemoglobin.html
2 Shaanan, B. Structure of human oxyhaemoglobin at 2.1 A resolution. (1983) J.Mol.Biol. (171) 31-59
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Salt Bridges in Deoxy Hb
Salt links (ionic interactions) between 2,3-BPG's negatively charged groups (2 phosphates and a
carboxyl group) and positively charged groups on the protein.
several basic groups (Lys and His R groups, and the N-terminal a-amino group) on BOTH b chains
Salt links effectively cross-link the quaternary structure across the central cavity in the T state.
Hb(BPG) [T state] + O2  Hb(O2) [R state] + BPG
http://employees.csbsju.edu/hjakubowski/classes/ch331/bind/olbindhemoglobin.html
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Oxygen-Hemoglobin binding
• Partial pressure of oxygen determines
how much oxygen binds.
• 2,3-BPG reduces Hb affinity to O2 and
increases O2 release in tissues.
• Small amount of CO reduces Hb ability
to transport O2 .
https://thechronicleflask.wordpress.com/tag/red-blood-cells/
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Mutations in hemoglobin (hemoglobinopathies):
Sickle cell anemia (Hb S):
1 Image: http://www.cc.nih.gov/ccc/ccnews/nov99/
2 Marengo-Rowe,A. J. (2006) Structure-function relations of human hemoglobins. Proc (Bayl Univ Med Cent)19(3) 239–
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245.
structure
PDB ID: 1GZX
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Hydrophobic pocket
PDB ID: 2HBS
Val6, Leu88 , Phe85
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Sickle cell trait (Hb AS)fights Malaria
1 Aidoo, M., Terlouw, D.J., Kolczak, M.S., McElroy, P.D., ter Kuile, F.O., Kariuki, S., Nahlen, B.L., Lal ,A.A., Udhayakumar, V.(2002)
Protective Effects of the Sickle Cell Gene Against Malaria Morbidity and Mortality. Lancet (359)1311-1312.
2 Luzzatto, L., Nwachuku-Jarrett, E.S., Reddy, S.( 1970) Increased sickling of parasitised erythrocytes as mechanism of resistance
against malaria in the sickle-cell trait. Lancet 1(7642) 319-321.
3 Gong, L., Parikh, S., Rosenthal, P.J. (2013) Biochemical and Immunological Mechanisms by Which Sickle Cell Trait Protects Against
Malaria. Malar J. 12(317).
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References
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Harrington, D.J., Adachi, K., Royer Jr., W.E. (1997) The high resolution crystal structure of deoxyhemoglobin S.
J.Mol.Biol. 272: 398-407
Shaanan, B. Structure of human oxyhaemoglobin at 2.1 A resolution. (1983) J.Mol.Biol. (171) 31-59
http://employees.csbsju.edu/hjakubowski/classes/ch331/bind/olbindhemoglobin.html
Marengo-Rowe,A. J. (2006) Structure-function relations of human hemoglobins. Proc (Bayl Univ Med Cent)19(3)
239–245.
Paoli, M., Liddington, R., Tame, J., Wilkinson, A., Dodson, G. (1996) Crystal structure of T state haemoglobin with
oxygen bound at all four haems. J.Mol.Biol. 256(4):775-92. PDB ID: 1BBB
Liddington, R., Derewenda, Z., Dodson, E., Hubbard,R, and Dodson, G. (1992) High resolution crystal
structures and comparisons of T-state deoxyhaemoglobin and two liganded T-state haemoglobins: T(alphaoxy)haemoglobin and T(met)haemoglobin. J Mol Biol. 228(2)551-79. PDB ID: 1HGA
Starr C., Taggart, R. (2001) Biology: The Unity and Diversity of Life (6th Ed.) pp. 183-227, Brooks/Cole, Pacific
Grove.
Rousseot, N., Jaenicke, E., Lamkemeyer, T., Harris, J.R., Pirow, R. (2006) Native and subunit
molecular mass
and quarternary structure of the hemoglobin from the primitive
branchiopod crustacean Triops cancriformis.
FEBS J 17, 4055-71.
Campbell, N.A., Reece, J.B., Taylor, M.R., Simon, E.J. (2006) Biology Concepts and Connections (Eds.) (5th Ed.) pp.
46-462, Pearson, San Francisco.
Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., Walter, P. (2002) Molecular Biology of the Cell. (Eds.), pp.
461, Garland Science, New York.
http://www.cc.nih.gov/ccc/ccnews/nov99/
Aidoo, M., Terlouw, D.J., Kolczak, M.S., McElroy, P.D., ter Kuile, F.O., Kariuki, S., Nahlen, B.L., Lal ,A.A.,
Udhayakumar, V.(2002) Protective Effects of the Sickle Cell Gene Against Malaria Morbidity and Mortality. Lancet
(359)1311-1312.
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