12
CASE FILES: BIOCHEMISTRY
(HbS), leading to sickle cell anemia, is a classic example of mutations that
affect protein structure.
Protein structure is typically classified as consisting of four levels:
primary
(
I0
),
secondary
(
II0
),
tertiary
(
IIIĀ°
), and
quaternary
(
IV0
).
Primary struc-
ture
is the
sequence of amino acids
in the protein.
Secondary structure
is
the
local three-dimensional spatial arrangement of amino acids that are
close to one another
in the primary sequence.
a-Helices and b-sheets
com-
pose the majority of secondary structures in all known proteins.
Tertiary
structure
is the
spatial arrangement of amino acid residues that are far
apart
in the linear primary sequence of a single polypeptide chain, and it
includes
disulfide bonds
and
noncovalent forces.
These noncovalent forces
include
hydrogen bonding,
which is also the primary stabilization force for
the formation of a-helices and P-sheets,
electrostatic interactions, van der
Waals forces,
and
hydrophobic effects. Quaternary structure
is the manner
in which
subunits of a multi-subunit protein are arranged
with respect to
one another.
Normal
hemoglobin has four subunits called globins.
Adult hemoglobin
has
two a (a1 and a2) and two b (b1 and b2) globin chains.
Each globin chain
has an associated heme prosthetic group, which is the site of oxygen binding
and release. All globin chains have similar primary sequences. The secondary
structure of globin chains consists of approximately
75 percent
a-helix. The
similar primary sequence promotes a similar tertiary structure in all globins
that is called the
globin fold,
which is compact and globular in overall con-
formation. The
quaternary structure of HbA can be described as a dimer
of a 1b1 and a2a2 dimers.
The aP dimers move relative to one another during
the binding and release of oxygen.
Hemoglobin must remain soluble
at high concentrations within the red
blood cell to support normal oxygen binding and release properties. This is made
possible by a distribution of
amino acid side chains
in which
hydrophobic
residues are sequestered in the interior core
of the folded globin subunits,
while
hydrophilic residues
dominate the
water-exposed surface
of the globin
fold. The disk-shaped heme prosthetic group is inserted into a hydrophobic
pocket formed by the globin.
Hemoglobin, and the homologous monomeric protein myoglobin (Mb),
both bind and release oxygen as a function of the surrounding concentration,
or partial pressure of oxygen. A plot of percent saturation of Hb or Mb with
oxygen versus the partial pressure of oxygen is called the oxygen dissociation
curve. Unlike Mb, which has a simple hyperbolic
oxygen dissociation curve
typical of ligand binding to a monomeric protein, the
quaternary structure
of HbA
allows it to bind oxygen with
positive cooperativity
giving a
sig-
moidal
oxygen dissociation curve (Figure 1-1). Essentially, binding of oxygen
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