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

Journal Article · Fri Nov 21 04:00:00 EST 2008 · Protein Sci.

DOI:https://doi.org/10.1110/ps.037234.108· OSTI ID:1006965

Pearce, Mary C; Morton, Craig J; Feil, Susanne C; Hansen, Guido; Adams, Julian J; Parker, Michael W; Bottomley, Stephen P ^[1]

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1. SVIMR-A

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.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1006965
• Journal Information: Protein Sci., Journal Name: Protein Sci. Journal Issue: (12) ; 12, 2008 Vol. 17
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
AGGLOMERATION
CITRATES
CONFORMATIONAL CHANGES
CRYSTAL STRUCTURE
DISEASES
EMPHYSEMA
HEPATITIS
HUMAN POPULATIONS
IONS
MOLECULES
POLYMERS
PROTEINS
STABILITY