The role of the acute-phase protein alpha 1-antichymotrypsin in brain dysfunction and injury.
The crystal structure of proteolytically modified human ACT has been solved at 2.7-A resolution (Baumann et al., 1991). The final model consists of 374 amino acids, 126 solvent molecules and 5 sugar residues. Asn70 is glycosylated and Asn104 is probably glycosylated. The role of carbohydrates in serpin function may be 3-fold: secretion, removal from circulation and recognition by receptors for complex uptake (Travis et al., 1990). Experiments with recombinant, non-glycosylated ACT have shown that glycosylation has no effect on the association rates of ACT with its target proteases (Rubin et al., 1990). The X-ray diffraction studies also revealed that a certain ACT region is involved in DNA binding, although the physiologic relevance of this binding is still unknown. Using a plethora of techniques, scientists are starting to understand the role of ACT in health and disease. It is 14 years since ACT was first purified (Travis et al., 1978) and 9 years since its gene was cloned (Chandra et al., 1983). We have learned considerably about this protease inhibitor in humans and rodents; in inflammation, cancer and AD; as binding to proteases (irreversibly), to the A beta (irreversibly) and to DNA. However, there are still open avenues for research. These include: finding the proteases that ACT inhibits in brain, identifying the cellular receptors which bind ACT-protease complexes and elucidating the DNA-binding phenomenon. Recently, 4 mutations have been found in APP. The first mutation at position 22 of A beta was detected in HCHWA-D by Levy et al. (1991).(ABSTRACT TRUNCATED AT 250 WORDS)
Abraham
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Arthritis Center, Boston, MA 02118.
D000210:Acute-Phase Reaction / Q000503:physiopathology; D000544:Alzheimer Disease / Q000276:immunology* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000686:Amyloidosis / Q000503:physiopathology; D000818:Animals; D001253:Astrocytes / Q000502:physiology; D001930:Brain Injuries / Q000276:immunology* / Q000378:metabolism; D000882:Haplorhini; D006801:Humans; D011480:Protease Inhibitors / Q000494:pharmacology; D000514:alpha 1-Antichymotrypsin / Q000502:physiology*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011480:Protease Inhibitors; D000514:alpha 1-Antichymotrypsin