Haemoglobin and haemoglobin genes Flashcards
Learning outcomes
• Revise the formed (cellular) elements of blood
• Be able to describe how the formed (cellular) elements of blood are derived from
haematopoietic stem cells
• Know that erythrocytes are specialised for oxygen transport
• Be aware of the various haemoglobin genes as a gene family
• Recognise that the expression of Hb genes change in fetal and adult erythrocytes
and the physiological importance of this phenomenon
• Know that fetal Hb has a higher O2
carrying capacity than adult Hb
• Be aware of the range of genetic diseases (haemoglobinopathies) associated with
mutations in haemoglobin genes.
• Have an understanding of sickle cell anaemia as a disease caused by a single point
mutation in a Hb gene.
• Have a basic understanding of the pathogenesis of sickle cell anaemia
What is the clinical relevance of haemoglobin?
• O2 the key to efficient ATP generation • Hence the need for effective O2 transport • The properties of O2 carrying proteins –Haemoglobins & myoglobin • Problems of O2 carriage –Haemoglobinopathies
Why are red blood cells a biconcave shape?
The biconcave shape of red cells provides a large surface area for the uptake and release
of oxygen and carbon dioxide.
How is erythrocyte function linked to the molecular shape of Hb?
O2 Transport
•depends on Hb in erythrocytes
•tetramer of 4 protein chains (the ‘globins’), each with
a haem group (porphyrin ring with a central Fe2+)
Adult Hb/ HbA consists of 2 alpha and 2 beta chains, with haem groups. (1 on each chain)
When oxygen binds to haem group the conformation is relaxed (oxyhaemoglobin), and tense when it is released (deoxyhaemoglobin)
How are the shape of proteins, including haemoglobin, specified?
• Only 20 types of amino acid used in proteins
• Linked by peptide bonds (hence polypeptides)
• Each type of protein has a unique sequence
• Polypeptide backbone and the sidechains
• The chemical properties of the component
amino acids DICTATE the shape of the
protein and its properties
• Structure relates to function
How does protein fold?
In conformation of lowest energy (high energy is unstable)-
• CONFORMATION: the final folded shape of
a protein
• Achieving the correct shape is not just about
thermodynamics-
Achieving this state involves active
involvement of other proteins called
MOLECULAR CHAPERONES
• These function to make the process efficient
and reliable
Hydrophobic forces fold this conformation in place
(hydrogen bonds, ionic bonds and VDWs- 3 non covalent bonds also involved)
(hydrophobic regions inside, polar regions outside)
What are the 4 levels of protein structure?
• Primary structure – The linear sequence of amino acids • Secondary structure – The folding and stabilisation (by H and other bonds) of the primary structure into regular elements (a helix & b sheet) • Tertiary structure – The folding and stabilisation of secondary structure into a 3D shape (+/- other small molecules) • Quaternary structure – Interaction of distinct polypeptide chains into oligomeric complexes (+/- other small molecules)
Linear amino acid chains- protein structure
N or Amino terminus
AA1 peptide bond AA2 AA3 AA4
AA5 AA6 . . . . . . . . . . . . . . . . . . AAn AAn+1 AAn+2
C or Carboxy terminus
Notes
• The gene encoding a given protein is ‘co linear’ with the protein
• Both genes and proteins have polarity
• The gene runs from 5’ to 3’ and the protein N terminus to C terminus
• In fact only a small proportion of the possible are actually used
• The possible number of polypeptide chains in enormous 20300 or ~10390
• Some types of sequence are used repeatedly in biology
What are the two key secondary structures involved in protein?
Alpha helix • Right handed corkscrew • Maintained by H bonds between peptide bonds • Some side chains destabilise alpha helix (PROLINE [too rigid] and GLYCINE [too flexible])
Beta sheet • Stretched out structure • H bonds between C-O and NH groups • Parallel or anti parallel Different proteins have different arrangements of a helix and b sheet
What bonds influence tertiary protein structure?
Covalent bonds influence the tertiary structure of protein- inter/intrachain disulfide bonds
Remember many proteins have a number of distinct regions/ DOMAINS
Families of proteins with a similar structure evolve from a common precursor
Gene families and haemoglobin
• Some genes are very similar
• Have probably evolved from an evolutionary
precursor by duplication
• Examples
– HOX genes : involved in development
– Intermediate filament genes : structural
• Often regulated in a coordinated manner
• Often arranged in clusters on a chromosome
– Grouped together
There are different combinations of haemoglobin genes which code for different variants of Hb
• HbF – Fetal haemoglobin α2g(gamma)2 • HbA – Adult haemoglobin α2β2 • HbS – Sickle cell haemoglobin α2β26 glu -Val
How can gene expression be restricted?
• Some genes are expressed in most cells
– e.g. genes whose protein products are
needed for core activities like metabolism
• Some genes are expressed in a highly
restricted manner
– Only in certain cell types
– Only in certain cell types are certain times
– Only in certain cell types under specific
conditions
Globin chain switching occurs through development- The composition changes as the concentration of
oxygen in the environment changes
Why change Hb gene expression during development?
• The Problem: – how to get oxygen transferred across placenta from maternal circulation to the fetus? • The Solution: – affinity of Hb for O2infetal red cells has to be greater than affinity of Hb in maternal red cells • How to do this? – Use different Hb proteins by using different Hb genes at different times
Haemoglobinopathies- Hb genes and disease
• Mutations in Hb genes leading to altered
amino acid sequences
– Altered properties of the Hb proteins
– Sickle cell anaemia
• Defective regulation of Hb gene expression
– Altered ratios of the Hb chains
– Altered properties of the complex
– The thalassaemias
Clinical relevance- sickle cell anaemia
A single mutation in the gene for a Hb
chain perturbs this shape and induces aggregation
of Hb molecules
and hence all the features of sickle cell anaemia
In the homozygous state
NB heterozygotes are near normal
