The membrane skeleton, a
protein lattice that laminates the internal side of the red cell membrane, contains four major
proteins:
spectrin, actin,
protein 4.1 and
ankyrin. By mass, the most abundant of these
proteins is
spectrin, a fibre-like
protein composed of two chains, alpha and beta, which are twisted along each other into a heterodimer. At their head region,
spectrin heterodimers are assembled into tetramers. At their distal end, these tetramers are interconnected into a two dimensional network by their linkage to oligomers of actin. This interaction is greatly strengthened by
protein 4.1. The skeleton is attached to the membrane by
ankyrin, a
protein that connects the
spectrin beta chain to the major transmembrane
protein band 3, the
anion channel
protein. Additional attachment sites are those of
protein 4.1 with several
glycoproteins, namely
glycophorin A and C, as well as direct interactions between
spectrin,
protein 4.1 and the negatively charged
lipids of the inner
membrane lipid bilayer.
Hereditary spherocytosis, elliptocytosis and pyropoikilocytosis represent a group of disorders that are due to deficiency or dysfunction of one of the membrane skeletal
proteins (Fig. 1). Known deficiency states include that of
spectrin,
ankyrin and
protein 4.1. Severe
spectrin and
ankyrin deficiencies (with decrease in
spectrin and
ankyrin contents to about 50% of the normal amount) are both rare disorders associated with severe autosomal recessive
hereditary spherocytosis. On the other hand, mild
spectrin deficiency is found in the majority of patients with autosomal dominant spherocytosis in which the degree of
spectrin deficiency correlates with the clinical severity of the disease.
Protein 4.1 deficiency, in contrast, is associated with
hereditary elliptocytosis, which in certain populations constitutes about 20% of all such patients. Known skeletal
protein dysfunctions include mutants of both alpha and
beta spectrin that involve the
spectrin heterodimer self-association site. These are clinically expressed as
hereditary elliptocytosis (HE) and a closely related disorder,
hereditary pyropoikilocytosis (
HPP). At the level of
protein function, this defect can be detected by analysis of the content of
spectrin dimers and tetramers in 0 degrees C low ionic strength extracts of red cell membranes. Their structural identification is accomplished by limited proteolytic digestion of
spectrin followed by two-dimensional tryptic
peptide mapping.(ABSTRACT TRUNCATED AT 400 WORDS)