Structure of follicle-stimulating hormone in complex with the entire ectodomain of its receptor

Xuliang Jiang, Heli Liu, Xiaoyan Chen, Po Han Chen, David Fischer, Venkataraman Sriraman, Henry N. Yu, Steve Arkinstall, Xiaolin He*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

157 Scopus citations

Abstract

FSH, a glycoprotein hormone, and the FSH receptor (FSHR), a G protein-coupled receptor, play central roles in human reproduction. We report the crystal structure of FSH in complex with the entire extracellular domain of FSHR (FSHRED), including the enigmatic hinge region that is responsible for signal specificity. Surprisingly, the hinge region does not form a separate structural unit as widely anticipated but is part of the integral structure of FSHRED. In addition to the known hormone-binding site, FSHRED provides interaction sites with the hormone: a sulfotyrosine (sTyr) site in the hinge region consistent with previous studies and a potential exosite resulting from putative receptor trimerization. Our structure, in comparison to others, suggests FSHR interacts with its ligand in two steps: ligand recruitment followed by sTyr recognition. FSH first binds to the high-affinity hormone-binding subdomain of FSHR and reshapes the ligand conformation to form a sTyr-binding pocket. FSHR then inserts its sTyr (i.e., sulfated Tyr335) into the FSH nascent pocket, eventually leading to receptor activation.

Original languageEnglish (US)
Pages (from-to)12491-12496
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number31
DOIs
StatePublished - Jul 31 2012

Keywords

  • CF3 motif
  • Leucine-rich repeat
  • Reproductive hormone
  • Signal transduction
  • Sulfated tyrosine recognition

ASJC Scopus subject areas

  • General

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