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Polymerization of human angiotensinogen: insights into its structural mechanism and functional significance
journal contribution
posted on 2023-06-07, 23:39 authored by Peter Stanley, Louise SerpellLouise Serpell, Penelope E SteinIn the present study, we have investigated the in vitro polymerization of human plasma AGT (angiotensinogen), a non-inhibitory member of the serpin (SERine Protease INhibitor) family. Polymerization of AGT is thought to contribute to a high molecular mass form of the protein in plasma that is increased in pregnancy and pregnancy-associated hypertension. The results of the present study demonstrate that the polymerization of AGT occurs through a novel mechanism which is primarily dependent on non-covalent linkages, while additional disulfide linkages formed after prolonged incubation are not essential for either formation or stability of polymers. We present the first analyses of AGT polymers by electron microscopy, CD spectroscopy, stability assays and sensitivity to proteinases and we conclude that their structure differs from the `loop-sheet¿ polymers typical of inhibitory serpins. Histidine residues within the unique N-terminal extension of AGT appear to influence polymer formation, although polymer formation can still take place after their removal by renin. At a functional level, we show that AGT polymers are not substrates for renin, so polymerization of AGT in plasma would predictably lead to decreased formation of AngI (angiotensin I) with blood pressure lowering. Polymerization may therefore be an appropriate response to hypertension. The ability of AGT to protect its renin cleavage site through polymerization may explain why the AngI decapeptide has remained linked to the large and apparently inactive serpin body throughout evolution.
History
Publication status
- Published
Journal
Biochemical JournalISSN
0264-6021Publisher
Portland PressExternal DOI
Issue
1Volume
400Page range
169-178Pages
10.0Department affiliated with
- Biochemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2012-02-06Usage metrics
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