TAILIEUCHUNG - Báo cáo khoa học: The loss of tryptophan 194 in antichymotrypsin lowers the kinetic barrier to misfolding

Antichymotrypsin, a member of the serpin superfamily, has been shown to form inactive polymers in vivo, leading to chronic obstructive pulmonary disease. At present, however, the molecular determinants underlying the polymerization transition are unclear. | ễFEBS Journal The loss of tryptophan 194 in antichymotrypsin lowers the kinetic barrier to misfolding Mary C. Pearce Lisa D. Cabrita Andrew M. Ellisdon and Stephen P. Bottomley Department of Biochemistry and Molecular Biology Monash University Clayton Australia Keywords antichymotrypsin protein aggregation protein misfolding serpin stability Correspondence S. P. Bottomley Department of Biochemistry and Molecular Biology PO Box 13D Monash University 3800 Australia Fax 61 3 99054699 Tel 61 3 99053703 E-mail Received 21 November 2006 revised 17 May 2007 accepted 23 May 2007 doi Antichymotrypsin a member of the serpin superfamily has been shown to form inactive polymers in vivo leading to chronic obstructive pulmonary disease. At present however the molecular determinants underlying the polymerization transition are unclear. Within a serpin the breach position is implicated in conformational change as it is the first point of contact for the reactive center loop and the body of the molecule. W194 situated within the breach represents one of the most highly conserved residues within the serpin architecture. Using a range of equilibrium and kinetic experiments the contribution of W194 to proteinase inhibition stability and polymerization was studied for antichymotrypsin. Replacement of W194 with phenylalanine resulted in a fully active inhibitor that was destabilized relative to the wild-type protein. The aggregation kinetics were significantly altered wild-type antichymotrypsin exhibits a lag phase followed by chain elongation. The loss of W194 almost entirely removed the lag phase and accelerated the elongation phase. On the basis of our data we propose that one of the main roles of W194 in antichymotrypsin is in preventing polymerization. The serpins serine proteinase inhibitors are a large family of metastable proteins with a highly conserved tertiary structure. Metastability of the serpin native .

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