Other Mechanisms of Serpin-related Disease
In humans, simple deficiency of many serpins (e.g., through a null mutation) may result in disease (see Table 1).
It is rare that single amino acid changes in the RCL of a serpin alters the specificity of the inhibitor and allow it to target the wrong protease. For example, the Antitrypsin-Pittsburgh mutation (methionine 358 to arginine) allowed the serpin to inhibit thrombin, thus causing a bleeding disorder.
Serpins are suicide inhibitors, the RCL acting as a "bait." Certain disease-linked mutations in the RCL of human serpins permit true substrate-like behaviour and cleavage without complex formation. Such variants are speculated to affect the rate or the extent of RCL insertion into the A-sheet. These mutations, in effect, result in serpin deficiency through a failure to properly control the target protease.
Several non-inhibitory serpins play key roles in important human diseases. For example, maspin functions as a tumour suppressor in breast and prostate cancer. The mechanism of maspin function remains to be fully understood. Murine knockouts of maspin are lethal; these data suggest that maspin plays a key role in development.
Read more about this topic: Serpin
Famous quotes containing the word disease:
“Smoking ... is downright dangerous. Most people who smoke will eventually contract a fatal disease and die. But they don’t brag about it, do they? Most people who ski, play professional football or drive race cars, will not die—at least not in the act—and yet they are the ones with the glamorous images, the expensive equipment and the mythic proportions. Why this should be I cannot say, unless it is simply that the average American does not know a daredevil when he sees one.”
—Fran Lebowitz (b. 1950)