PMID- 21525003
OWN - NLM
STAT- MEDLINE
DCOM- 20110830
LR  - 20211020
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 286
IP  - 25
DP  - 2011 Jun 24
TI  - Defining structural and functional dimensions of the extracellular thyrotropin 
      receptor region.
PG  - 22622-31
LID - 10.1074/jbc.M110.211193 [doi]
AB  - The extracellular region of the thyrotropin receptor (TSHR) can be subdivided 
      into the leucine-rich repeat domain (LRRD) and the hinge region. Both the LRRD 
      and the hinge region interact with thyrotropin (TSH) or autoantibodies. 
      Structural data for the TSHR LRRD were previously determined by crystallization 
      (amino acids Glu(30)-Thr(257), 10 repeats), but the structure of the hinge region 
      is still undefined. Of note, the amino acid sequence (Trp(258)-Tyr(279)) 
      following the crystallized LRRD comprises a pattern typical for leucine-rich 
      repeats with conserved hydrophobic side chains stabilizing the repeat fold. 
      Moreover, functional data for amino acids between the LRRD and the transmembrane 
      domain were fragmentary. We therefore investigated systematically these TSHR 
      regions by mutagenesis to reveal insights into their functional contribution and 
      potential structural features. We found that mutations of conserved hydrophobic 
      residues between Thr(257) and Tyr(279) cause TSHR misfold, which supports a 
      structural fold of this peptide, probably as an additional leucine-rich repeat. 
      Furthermore, we identified several new mutations of hydrophilic amino acids in 
      the entire hinge region leading to partial TSHR inactivation, indicating that 
      these positions are important for intramolecular signal transduction. In summary, 
      we provide new information regarding the structural features and functionalities 
      of extracellular TSHR regions. Based on these insights and in context with 
      previous results, we suggest an extracellular activation mechanism that supports 
      an intramolecular agonistic unit as a central switch for activating effects at 
      the extracellular region toward the serpentine domain.
FAU - Kleinau, Gunnar
AU  - Kleinau G
AD  - Department for Structural Biology, Leibniz-Institut fur Molekulare Pharmakologie, 
      D-13125 Berlin, Germany.
FAU - Mueller, Sandra
AU  - Mueller S
FAU - Jaeschke, Holger
AU  - Jaeschke H
FAU - Grzesik, Paul
AU  - Grzesik P
FAU - Neumann, Susanne
AU  - Neumann S
FAU - Diehl, Anne
AU  - Diehl A
FAU - Paschke, Ralf
AU  - Paschke R
FAU - Krause, Gerd
AU  - Krause G
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110427
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Inositol Phosphates)
RN  - 0 (Receptors, Thyrotropin)
RN  - 9002-71-5 (Thyrotropin)
RN  - E0399OZS9N (Cyclic AMP)
SB  - IM
MH  - Amino Acid Sequence
MH  - Amino Acid Substitution
MH  - Animals
MH  - COS Cells
MH  - Cattle
MH  - Chlorocebus aethiops
MH  - Conserved Sequence
MH  - Cyclic AMP/metabolism
MH  - Extracellular Space/*metabolism
MH  - Gene Expression Regulation
MH  - Humans
MH  - Hydrophobic and Hydrophilic Interactions
MH  - Inositol Phosphates/metabolism
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Mutagenesis, Site-Directed
MH  - Mutation
MH  - Protein Folding
MH  - Protein Structure, Secondary
MH  - Protein Structure, Tertiary
MH  - Receptors, Thyrotropin/*chemistry/genetics/*metabolism
MH  - Thyrotropin/metabolism
PMC - PMC3121406
EDAT- 2011/04/29 06:00
MHDA- 2011/08/31 06:00
PMCR- 2012/06/24
CRDT- 2011/04/29 06:00
PHST- 2011/04/29 06:00 [entrez]
PHST- 2011/04/29 06:00 [pubmed]
PHST- 2011/08/31 06:00 [medline]
PHST- 2012/06/24 00:00 [pmc-release]
AID - S0021-9258(19)48970-9 [pii]
AID - M110.211193 [pii]
AID - 10.1074/jbc.M110.211193 [doi]
PST - ppublish
SO  - J Biol Chem. 2011 Jun 24;286(25):22622-31. doi: 10.1074/jbc.M110.211193. Epub 
      2011 Apr 27.