Characterization of T(4)-binding globulin cleaved by human leukocyte elastase.
T(4)-binding globulin (TBG) serves to maintain an important serum pool of thyroid hormones and to prevent their excessive loss in urine. TBG has also been implicated in the tissue distribution and targeted delivery of the hormones, the mechanisms of which remain unclear. By virtue of sequence homology, TBG belongs to the serine proteinase inhibitors superfamily of proteins that are characterized by a reactive site loop serving as a recognition site for serine proteinases. However, both TBG and another serpin with hormone transport function, corticosteroid-binding globulin, are noninhibitory. Cleavage of corticosteroid-binding globulin by human leukocyte elastase results in the reduction of its hormone-binding affinity and capacity. In this communication we confirm previous observations that TBG is also cleaved by elastase and undergoes the characteristic conformational changes. In addition, contrary to a previous report, the present work demonstrates that the cleaved product has reduced T(4)-binding affinity and, as expected, increased heat stability. Additional fragmentation of the molecule results in the loss of the hormone-binding site that is in agreement with a recent in vivo observation of apparent consumption at sites of inflammation. These data suggest that TBG may play a role in the targeted delivery of thyroid hormones to tissues rich in proteinases.
Janssen
Onno E
OE
Department of Medicine, University of Essen, D-45122 Essen, Germany. onno.janssen@uni-essen.de
Golcher
Henriette M B
HM
Grasberger
Helmut
H
Saller
Bernhard
B
Mann
Klaus
K
Refetoff
Samuel
S
D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D004355:Drug Stability; D006358:Hot Temperature; D006801:Humans; D019272:Leukocyte Elastase / Q000494:pharmacology*; D007962:Leukocytes / Q000378:metabolism; D011863:Radioimmunoassay; D013974:Thyroxine / Q000378:metabolism; D013975:Thyroxine-Binding Proteins / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology*
D013975:Thyroxine-Binding Proteins; D019272:Leukocyte Elastase; D013974:Thyroxine