PMID- 23300822
OWN - NLM
STAT- MEDLINE
DCOM- 20130624
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 12
DP  - 2012
TI  - Extended and structurally supported insights into extracellular hormone binding, 
      signal transduction and organization of the thyrotropin receptor.
PG  - e52920
LID - 10.1371/journal.pone.0052920 [doi]
LID - e52920
AB  - The hormone thyrotropin (TSH) and its receptor (TSHR) are crucial for the growth 
      and function of the thyroid gland. The TSHR is evolutionary linked with the 
      receptors of follitropin (FSHR) and lutropin/choriogonadotropin (LHR) and their 
      sequences and structures are similar. The extracellular region of TSHR contains 
      more than 350 amino acids and binds hormone and antibodies. Several important 
      questions related to functions and mechanisms of TSHR are still not 
      comprehensively understood. One major reason for these open questions is the lack 
      of any structural information about the extracellular segment of TSHR that 
      connects the N-terminal leucine-rich repeat domain (LRRD) with the transmembrane 
      helix (TMH) 1, the hinge region. It has been shown experimentally that this 
      segment is important for fine tuning of signaling and ligand interactions. A new 
      crystal structure containing most of the extracellular hFSHR region in complex 
      with hFSH has recently been published. Now, we have applied these new structural 
      insights to the homologous TSHR and have generated a structural model of the TSHR 
      LRRD/hinge-region/TSH complex. This structural model is combined and evaluated 
      with experimental data including hormone binding (bTSH, hTSH, thyrostimulin), 
      super-agonistic effects, antibody interactions and signaling regulation. These 
      studies and consideration of significant and non-significant amino acids have led 
      to a new description of mechanisms at the TSHR, including ligand-induced 
      displacements of specific hinge region fragments. This event triggers 
      conformational changes at a convergent center of the LRRD and the hinge region, 
      activating an "intramolecular agonistic unit" close to the transmembrane domain.
FAU - Krause, Gerd
AU  - Krause G
AD  - Leibniz-Institut fur Molekulare Pharmakologie, Berlin, Germany.
FAU - Kreuchwig, Annika
AU  - Kreuchwig A
FAU - Kleinau, Gunnar
AU  - Kleinau G
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20121227
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Receptors, Thyrotropin)
RN  - 9002-71-5 (Thyrotropin)
SB  - IM
MH  - Animals
MH  - Humans
MH  - *Models, Molecular
MH  - Protein Binding
MH  - Protein Structure, Secondary
MH  - Protein Structure, Tertiary
MH  - Receptors, Thyrotropin/chemistry/*metabolism
MH  - Signal Transduction/*physiology
MH  - Thyrotropin/chemistry/*metabolism
PMC - PMC3531376
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/01/10 06:00
MHDA- 2013/06/26 06:00
PMCR- 2012/12/27
CRDT- 2013/01/10 06:00
PHST- 2012/10/01 00:00 [received]
PHST- 2012/11/23 00:00 [accepted]
PHST- 2013/01/10 06:00 [entrez]
PHST- 2013/01/10 06:00 [pubmed]
PHST- 2013/06/26 06:00 [medline]
PHST- 2012/12/27 00:00 [pmc-release]
AID - PONE-D-12-30077 [pii]
AID - 10.1371/journal.pone.0052920 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(12):e52920. doi: 10.1371/journal.pone.0052920. Epub 2012 Dec 27.