Loop variants of the serpin thyroxine-binding globulin: implications for hormone release upon limited proteolysis

The Biochemical Journal
Helmut GrasbergerOnno E Janssen

Abstract

Thyroxine-binding globulin (TBG) and corticosteroid-binding globulin are unique among non-inhibitory members of the superfamily of serine-proteinase inhibitors (serpins) in undergoing a dramatic increase in stability [stressed-to-relaxed (S-->R) transition] after proteolytic cleavage within their exposed reactive-site-loop (RSL) equivalent. This structural rearrangement involves the insertion of the cleaved loop as a new strand into the beta-sheet A and is accompanied by a decrease in hormone binding. To define the mechanism that leads to disruption of hormone binding of TBG after proteolytic cleavage, the effect of partial loop deletions and replacements by the alpha(1)-proteinase inhibitor homologues of TBG were evaluated. Unexpectedly, deletion of the loop's C-terminus, thought to be important for thyroxine binding, improved the binding affinity over that of normal TBG. Proteolytic cleavage of this variant revealed an intact S-->R transition and reduced its binding activity to that of cleaved TBG. In contrast, a chimaera with C-terminal loop extension mimicked the decreased binding affinity of cleaved TBG and had a thermal stability intermediate between that of native and cleaved serpins. This variant was still susceptible t...Continue Reading

Citations

Feb 18, 2011·The Journal of Biological Chemistry·Xiaoqiang QiAiwu Zhou
Jan 31, 2014·Proceedings. Biological Sciences·Xiaoqiang QiRobin W Carrell
Aug 30, 2006·Proceedings of the National Academy of Sciences of the United States of America·Aiwu ZhouRobin W Carrell
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Jun 3, 2008·Journal of Molecular Biology·Aiwu ZhouRobin W Carrell
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