In sickle cell hemoglobin, fiber formation occurs when
molecules stick together.
This process happens in sickle cell hemoglobin because of the
genetic mutation that leads to a change in a single
amino acid residue
of the protein sequence. In
sickle cell hemoglobin the changed or mutated amino acid is
The literal meaning of hydrophobic is 'fear of water.' This is not
exactly the case in hemoglobin.
amino acid change occurs on the surface of the sickle cell hemoglobin
Since the cellular environment of red blood cells is similar to
water, the amino acid change causes the hemoglobin to associate with other
hemoglobin molecules rather than with the cellular environment.
This preferential interaction of the hemoglobin molecules with each other
rather than water is attributed to a 'hydrophobic interaction' of certain
amino acid residues, one of which is the mutated residue, b6
This figure (left) depicts the
interaction between hemoglobin molecules that is thought to drive
fiber formation. The amino acid residues
interact with each other, b6
Valine, b85 Phenylalanine and b88
Leucine, are shown in blue.
The b6 Valine comes from one
subunit from one hemoglobin while the b85 Phenylalanine and b88
Leucine residues come from a b subunit of
a different hemoglobin molecule. Also shown are heme groups
with coordinating His residues (maroon).
deeper: hydrophobic interactions of amino acids
formation only occurs in the deoxy or T-state.
Because of the structural change to form the T-state, a different
region of the protein exposes a hydrophobic surface area.
The area containing the mutated amino acid residue and the area
exposed by forming the T-state associate together to form the fibers.
molecules associate into double strands and then, seven of these strands
associate together to form a fiber.
Hemoglobin (HbS) in T- State
|In this figure the hemoglobin
tetramer is represented as a circle, such that one quarter
corresponds to one protein subunit. The b6
mutation is indicated as a protrusion from the circle in the b2
subunit and the hydrophobic pocket is a nick in the b1
||In this figure the
interaction of different Hb S tetramers to form the fibers is
shown. The tetramers must be in the deoxy state in order
for the fibers to form. As can be seen from the diagram,
subunit can either participate as a donor or
acceptor in the interaction, but cannot do both.
||These fibers then associate with
each other forming larger and larger fibers over time.
These fibers can be observed using a technique called
microscopy. The double
strands of sickle cell hemoglobin fibers have been observed using
crystallography. (Fig 4.5)
|FIG 4.5 electron
micrograph of fiber with heterogeneous nucleation
formation occurs through two main stages, referred to as the double
nucleation mechanism (Fig 4.6). In the
first stage individual hemoglobin molecules have to come together to form
a nucleus, that will be the initiation point for the fibers.
Approximately, seven hemoglobin molecules need to come together to
form this nucleus. This
process is relatively slow, because of the number of molecules that need
to come together to form the nucleus.
Once the nucleus is formed the second stage of the process begins.
In this second stage, fiber formation is relatively rapid because
fibers can build on the pre-existing structure.
Practically, this means that it is not necessary to bring so many
molecules together at once, which significantly speeds up the process.
FIG 4.6 Double
graphic shows the two stages of fiber formation
upper half -1st stage; lower half - 2nd stage
image taken from
laboratory is interested in understanding the mechanics of the first or
initial stage of the fiber formation process.
If this process can be extended to match that of the circulation
time in the body, then the Red Blood Cells (RBCs) would become exposed to oxygen before a
significant amount of fibers could form.
We believe that this would be extremely beneficial in the treatment
of sickle cell disease. (link to the research pages)
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