Adapter Proteins Link Actin Filaments to Membranes

To contribute to the structure of cells and to harness the power of actin polymerization, actin filaments are very often attached to membranes or associated with intracellular structures. Actin filaments are especially abundant in the cell cortex underlying the plasma membrane, to which they give support. Actin filaments can interact with membranes either laterally or at their ends.

Our first example of actin filaments attached to a membrane involves the human erythrocyte—the red blood cell. The erythrocyte consists essentially of a plasma membrane enclosing a high concentration of the protein hemoglobin. It functions in the transport of oxygen from the lungs to tissues and of carbon dioxide from tissues back to the lungs—all powered by the magnificent muscle known as the heart. Erythrocytes must be able to survive the raging torrents of blood flow in the heart, then flow down arteries and survive squeezing through narrow capillaries before being cycled through the lungs via the heart. To survive this grueling process for thousands of cycles, erythrocytes have a based network underlying the plasma membrane that gives them both the tensile strength and the flexibility necessary for their journey. This network is based on short actin filaments about 14 subunits in length, stabilized on their sides by tropomyosin (discussed in more detail in Section 17.6) and by the capping protein tropomodulin on the (−) end. These short filaments serve as hubs for binding about six flexible spectrin molecules, generating a fishnet-like structure (Figure 17-21a) that provides both strength and flexibility. The spectrin molecules are attached to membrane proteins through two mechanisms: through a protein called ankyrin to the bicarbonate transporter (a transmembrane protein also known as band 3), and through a spectrin- and F-actin–binding protein called band 4.1 to another transmembrane protein called glycophorin C (Figure 17-21b). Although this spectrin-based network is highly developed in erythrocytes, similar types of linkages occur in many cell types. For example, a related type of ankyrin-spectrin attachment links the Na+/K+ ATPase to the actin cytoskeleton on the basolateral membrane of epithelial cells.

794

795

Genetic defects in proteins of the red blood cell cytoskeleton can result in cells that rupture easily, giving rise to diseases known as hereditary spherocytic anemias (spherocytic because the cells are rounder, anemias because there is a shortage of red blood cells) and hence a shorter life span. In human patients, mutations in spectrin, band 4.1, and ankyrin can cause these diseases.

Microfilaments also provide the support for cell-surface structures such as microvilli and membrane ruffles. If we look at a microvillus, it is clear that its actin filaments must have an end-on attachment at the tip and lateral attachments down its length. What is the orientation of actin filaments in microvilli? Decoration experiments show that the (+) end is at the tip. Moreover, when fluorescent actin is added to a cell, it is incorporated at the tip of a microvillus, showing not only that the (+) end is there, but also that actin filament assembly occurs there (Figure 17-21c). It is not yet known how actin filaments are attached at the microvillus tip or how assembly is regulated there. This (+) end orientation of actin filaments with respect to the plasma membrane is found almost universally—not just in microvilli, but also, for example, in the leading edges of motile cells. The lateral attachments to the plasma membrane are provided, at least in part, by the ERM (ezrin-radixin-moesin) family of proteins. This family consists of regulated proteins that exist in a folded, inactive form. When locally activated by phosphorylation in response to an external signal, the F-actin–binding and membrane protein–binding sites of the ERM protein are exposed to provide a lateral linkage to actin filaments (Figure 17-21d). ERM proteins can link the actin filaments to the cytoplasmic domain of membrane proteins directly or indirectly through scaffolding proteins.

796

The types of actin-membrane linkages we have discussed so far do not involve areas of the plasma membrane attached directly to other cells in a tissue or to the extracellular matrix, but such linkages do exist. Contact between epithelial cells is mediated by highly specialized regions of the plasma membrane called adherens junctions (see Figure 17-1b). Other specialized regions of association called focal adhesions mediate attachment of cells to the extracellular matrix. In turn, these specialized types of attachments connect to the cytoskeleton, as will be described in more detail when we discuss cell migration (Section 17.7) and cells in the context of tissues (see Chapter 20).

Muscular dystrophies are genetic diseases that are often characterized by the progressive weakening of skeletal muscle. One of these genetic diseases, Duchenne muscular dystrophy, affects the protein dystrophin, whose gene is located on the X chromosome, so the disease is much more prevalent in males than in females. Dystrophin is a modular protein whose function is to link the cortical actin network of muscle cells to a complex of membrane proteins that link to the extracellular matrix. Thus dystrophin has an N-terminal actin-binding domain, followed by a series of spectrin-like repeats, and terminates in a domain that binds the transmembrane dystroglycan complex to the extracellular matrix protein laminin (see Figure 17-20a and Figure 1-31). In the absence of dystrophin, the plasma membrane of muscle cells becomes weakened by cycles of muscle contraction and eventually ruptures, resulting in death of the muscle fibers.