Preventing serpin aggregation: The molecular mechanism of citrate action upon antitrypsin unfolding

Mary Catherine Pearce, Craig J Morton, Susanne C Feil, Guido Hansen, Julian J Adams, Michael W Parker, Stephen Paul Bottomley

Research output: Contribution to journalArticleResearchpeer-review

17 Citations (Scopus)

Abstract

The aggregation of antitrypsin into polymers is one of the causes of neonatal hepatitis, cirrhosis and emphysema. A similar reaction resulting in disease can occur in other human serpins and collectively they are known as the serpinopathies. One possible therapeutic strategy involves inhibiting the conformational changes involved in antitrypsin aggregation. The citrate ion has previously been shown to prevent antitrypsin aggregation and maintain the protein in an active conformation; its mechanism of action however is unknown. Here we demonstrate that the citrate ion prevents the initial misfolding of the native state to a polymerogenic intermediate in a concentration dependent manner. Furthermore, we have solved the crystal structure of citrate bound to antitrypsin and show that a single citrate molecule binds in a pocket between the A and B beta-sheets, a region known to be important in maintaining antitrypsin stability.
Original languageEnglish
Pages (from-to)2127 - 2133
Number of pages7
JournalProtein Science
Volume17
Issue number12
Publication statusPublished - 2008

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