164
chapter 10
Heteropolysaccharides I: Glycoproteins and Glycolipids
not react with desialylated glycophorins, the M and N
blood group specificities reside in the sequences at the
amino terminus of glycophorins N and B. The red blood
cell membrane contains a number of other proteins, which
have been separated and characterized into
1 0 - 1 2
ma-
jor components by polyacrylamide gel electrophoresis in
sodium dodecyl sulfate (Chapter 2). A schematic illus-
tration of electrophoretic patterns of the major red blood
cell membrane proteins and of membrane skeletal proteins
is shown in Figure 10-12; their properties are given in
Table 10-3.
Normal red blood cells are deformable biconcave disks.
Their shape is determined by the external environment of
the cell, the metabolic activity of the cell, the nature of
hemoglobin, the membrane skeleton (see below), and the
age of the cell. A normal human red blood cell has a life
span of about
1 2 0
days and travels a distance of about
175 miles. Much of this travel occurs in capillary channels
of the microcirculation, where flow rates are very slow.
Here, particularly at branch points, the shape of the cell
undergoes striking deformations and can squeeze through
openings as small as one-twentieth the cell diameter. Thus,
the primary determinant of blood flow and viscosity is
Spectrin
Ankyrin
Anion
exchange
protein
3 —1
4.T
4.2
Actin
G3PD
PAS-1, (GRA
)2
PAS-4, GPA-GPB
r (GPB
)2
PAS-2,
GPA
L GPC
7 —
8
-
RAS-3, GPB
Globin
CB
M
PAS
FIGURE 10-12
Schematic representations of sodium dodecyl sulfate polyacrylamide gel
electrophoretic patterns of red blood cell membranes (M) and membrane
skeletons (S), based on work by Fairbanks and Steck. Proteins are stained
with Coomassie blue (CB) and sialoglycoproteins with periodic
acid-Schiff (PAS). GPA, GPB, and GPC are glycophorin A, B, and C,
respectively; G3PD is glyceraldehyde-3-phosphate dehydrogenase. (GPA
)2
and (GPB
)2
are dimers, and GPA-GPB is a heterodimer. [Reproduced with
permission from J. B. Stanbury, J. B. Wyngaarden, D. S. Fredrickson, et al.
(Eds.),
T h e M eta b o lic B a sis o f In h e rite d D isea se
, 5th ed. McGraw-Hill,
New York, 1983.]
red blood cell membrane deformability. Abnormalities of
vascular channels (e.g., presence of platelet clumps and
fibrin strands) and intrinsic defects in red blood cells (e.g.,
presence of abnormal hemoglobins; Chapter 28) can alter
the dynamics of the red cell shape, affect the oxygen supply
to the tissue being traversed, and reduce their own life span.
The red blood cell’s durability and flexibility are due to
its submembranous protein network, the
m em b ra n e sk ele-
ton.
The membrane skeleton consists predominantly of
four proteins:
sp ectrin , actin , p ro te in 4.1,
and
an kyrin
(also known as
syn d ein )
(Figure 10-13). Spectrin, an ex-
trinsic protein located on the cytoplasmic surface of the
membrane, was so named because of its extraction from
red blood cell ghosts (specters). It constitutes about 25%
by weight of the membrane proteins. Spectrin is a long and
unusually flexible molecule consisting of two structurally
and functionally distinct polypeptide chains
(a
and
/3)
aligned side by side to form a heterodimer. It assumes a
variety of conformations that may be essential for pliancy
and deformability. The lateral connections of spectrin are
established by head-to-head association of heterodimers to
form heterotetramers or perhaps higher order oligomers.
Spectrin can also bind at one end to short filaments of actin
consisting of 10-20 monomers. The monomer is known as
G-actin and the polymer as F-actin. Actin is present in all
eukaryotic cells, and its role in muscle contraction is well
established (Chapter 21). The spectrin-actin interaction is
cooperatively strengthened by protein 4.1, a globular pro-
tein that binds to spectrin at the tail end of the molecule
in close proximity to the actin binding site. Spectrin is
attached to the inner membrane surface by means of two
proteins:
ankyrin
(from the Greek word for
“anchor”),
or
syndein
(from the Greek word for
“binding together”),
and anion exchange protein (protein 3). Spectrin is bound
to ankyrin, a large protein of pyramidal shape, which teth-
ers the membrane skeleton via its connection to the an-
ion exchange protein. The latter is an integral membrane
glycoprotein that spans the lipid bilayer and functions in
exchange of Cl- for HCOj" (Chapter 1). Protein 4.1 may
also bind the actin-spectrin complex to the transmembrane
glycoprotein glycophorin.
The
intricate
interactions
of
the
spectrin-protein
4.1-actin complex may be of central importance in main-
taining the structural integrity of the red cell membrane.
Two genetic disorders affecting the red cell membrane
skeleton are
h ered ita ry sp h ero cyto sis
and
h ereditary
elliptocytosis.
The former, the most common congenital
form of hemolytic anemia in persons of northern Euro-
pean descent, exhibits an autosomal dominant inheritance
pattern. The red blood cells are spherical, osmotically frag-
ile, and considerably reduced in life span. They undergo
