lysosomal storage diseases involve deficiencies in one or other of the enzymes required to degrade the complex glycosylated proteins and lipids found on cell surfaces.
Tay‐Sachs disease involves severe mental retardation and blindness, with death by the age of three. In this case an enzyme required to break down a particular complex membrane lipid called a ganglioside is missing and undegraded ganglioside accumulates, swelling the lysosomes. Gangliosides are especially important in neuronal membranes so neurons are particularly damaged.
Although organelles compartmentalize cell activity they do not work in isolation. Similarly, cells often function as a collective. Organelles and cells form both intracellular and intercellular junctions to facilitate this. We will consider both these in turn.
Organelle Junctions
Organelles form junctions with other organelles and the plasma membrane via specialized structures known as membrane contact sites. Membrane contact sites are regions of close apposition whereby the membranes on either side of the junction are separated by <30 nm. They are stabilized by tethering proteins that span the junction.
The ER is a particularly well‐connected organelle. It forms membrane contact sites with most organelles, including lysosomes (Figure 2.5), as well as with the plasma membrane. ER membrane contact sites are often tethered by a protein called VAP (VAP is short for the cumbersome name “vesicle‐associated membrane protein associated protein”!). VAPs are integral proteins of the ER that recognize and bind to specific target proteins on the apposing membrane (page 120). This is an example of a protein–protein interaction and we will meet many other examples throughout this book.
Membrane contact sites serve a variety of functions. They are important for the trafficking of lipids around the cell and in the transfer of calcium between compartments, for example between the ER and mitochondria.
Source: Images by Bethan S. Kilpatrick, Clare E. Futter, and Sandip Patel, University College London. Reproduced by permission.
Cell Junctions
In multicellular organisms, and particularly in their epithelia, it is often necessary for neighboring cells within a tissue to be connected. This function is provided by cell junctions. In animal cells there are three types of junction. Those that form a tight seal between adjacent cells are known as tight junctions; those that allow communication between cells are known as gap junctions. A third class of cell junction anchors cells together, allowing the tissue to be stretched without tearing. These are called anchoring junctions.
Tight junctions are found wherever the flow of extracellular medium is to be restricted and are particularly common in epithelial cells, such as those lining the small intestine. The plasma membranes of adjacent cells are pressed together so tightly that no intercellular space exists between them (Figure 1.6 on page 9). Tight junctions between the epithelial cells of the intestine ensure that the only way that molecules can get from the lumen of the intestine to the blood supply that lies beneath is by passing through the cells, a route that can be selective.
Gap junctions are specialized structures that allow cell‐to‐cell communication in animals (Figure 2.6). When two cells form a gap junction, ions and small molecules can pass directly from the cytosol of one cell to the cytosol of the other cell without going into the extracellular medium. Since ions can move through the junction, changes in electrical voltage are also rapidly transmitted from cell to cell by this route. In vertebrates, the structure that makes this possible is the connexon. When two compatible connexons meet, they form a tube, about 1.5 nm in diameter, that runs through the plasma membrane of the first cell, across the small gap between the cells, and through the plasma membrane of the second cell. This hole is large enough to allow through small organic molecules as well as ions, but it is too small for proteins or nucleic acids. The limit is a relative molecular mass (Mr) of about 1000. Gap junctions are especially important in the heart, where they allow an electrical signal to pass rapidly between all the cardiac muscle cells, ensuring that they all contract at the appropriate time. Each connexon is composed of six protein subunits called connexins that can twist against each other to open and close the central channel in a process called gating (page 147). This allows the cell to control the degree to which it shares material with its neighbor.
IN DEPTH 2.2 MY OLD MAM
The existence of membrane contact sites between the ER and mitochondria has been known for decades from electron microscope studies. Relatively recently, these contacts have been isolated biochemically from cell extracts for study. The resulting fractions are referred to as mitochondria‐associated membranes (MAMs ) because they contain proteins not only typically found in mitochondrial membranes but also in the ER. In live cells, ER‐mitochondria contact sites provide a restricted space such that when calcium ions are released from the ER (Chapter 10), they achieve a very high local concentration that facilitates their uptake by adjacent mitochondria.
Example 2.2 Gap Junctions Keep Eggs Healthy
In the days leading up to ovulation, oocytes develop within structures called follicles, in which they are connected to surrounding granulosa cells by gap junctions. During their development oocytes are not yet themselves capable of performing several fundamental homeostatic processes, such as regulating intracellular pH. However, the surrounding granulosa cells have ample ability to regulate pH, and H+ ions can pass through the gap junctions, such that the granulosa cells effectively regulate the pH of the oocyte on its behalf. By the time the oocyte is fully grown and ready to be ovulated it can finally regulate its own pH, at which time it jettisons the granulosa cells and becomes ready to be fertilized by a spermatozoon.
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