High resolution crystal structures of piscine transthyretin reveal different binding modes for triiodothyronine and thyroxine.
Transthyretin (TTR) is an extracellular transport protein involved in the distribution of thyroid hormones and vitamin A. So far, TTR has only been found in vertebrates, of which piscine TTR displays the lowest sequence identity with human TTR (47%). Human and piscine TTR bind both thyroid hormones 3,5,3'-triiodo-l-thyronine (T(3)) and 3,5,3',5'-tetraiodo-l-thyronine (thyroxine, T(4)). Human TTR has higher affinity for T(4) than T(3), whereas the reverse holds for piscine TTR. X-ray structures of Sparus aurata (sea bream) TTR have been determined as the apo-protein at 1.75 A resolution and bound to ligands T(3) and T(4), both at 1.9 A resolution. The apo structure is similar to human TTR with structural changes only at beta-strand D. This strand forms an extended loop conformation similar to the one in chicken TTR. The piscine TTR.T(4) complex shows the T(4)-binding site to be similar but not identical to human TTR, whereas the TTR.T(3) complex shows the I3' halogen situated at the site normally occupied by the hydroxyl group of T(4). The significantly wider entrance of the hormone-binding channel in sea bream TTR, in combination with its narrower cavity, provides a structural explanation for the different binding affinities of human and piscine TTR to T(3) and T(4).
Eneqvist
Therese
T
Umea Centre for Molecular Pathogenesis, Umea University, SE-901 87 Umea, Sweden.
Lundberg
Erik
E
Karlsson
Anders
A
Huang
Shenghua
S
Santos
Cecília R A
CR
Power
Deborah M
DM
Sauer-Eriksson
A Elisabeth
AE
D000818:Animals; D002645:Chickens; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011228:Prealbumin / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D021541:Sea Bream; D013974:Thyroxine / Q000737:chemistry*; D014284:Triiodothyronine / Q000737:chemistry*
D008024:Ligands; D011228:Prealbumin; D014284:Triiodothyronine; D013974:Thyroxine