The Cysteine-rich C-Flanking Region of the Thyrotropin Receptor has Very Ancient Phylogenetic Origins: Implications from Sequence Analysis

V. Kaczur, N. R. Farid, I. A. Racz, A. Szendroi, M. Takács, V. Kaczur, V. Kaczur, Nadir R. Farid

Research output: Contribution to journalArticle


The thyrotropin receptor (TSHR) is a member of a rapidly expanding family of leucine-rich repeat (LRR)-containing G protein-coupled receptors (LGRs). These arose as the result of the union of an LRR module with a bared-down G protein-coupled signaling unit (signalon). The cysteine-rich C-flanking region (CFR) connects these two modules. The TSHR stands out from other glycoprotein hormone receptors by virtue of a 50 residue 'insertion' in its CFR. This CFR 'add on' sequence (CFLANS) is apparently essential for receptor ectodomain cleavage, characteristic of TSHR. To find out whether the CFLANS was a recent evolutionary innovation in TSHR or had deep evolutionary history, we compared the protein sequences of 13 LGRs and submitted them to phylogenetic analysis. The phylogentic tree based on complete LGR sequences was consistent with the evolutionary record and suggested that a TSHR-like structure was evolutionarily the most preserved. CFLANS could be found in the earliest form of life for which the presence of LGRs was documented, the sea anemone. CFRs with homology to TSHR CFLANS have been found in C. elegans and two D. melanogaster LGRs. The evolutionary line leading to vertebrates suggests that the root structure probably possessed a CFR not unlike that in TSHR. The descent of various LGRs suggests that the follicle-stimulating hormone receptor (FSHR) separated earlier than the luteinizing hormone receptor (LHR). The closer relatedness of LHR to TSHR is consistent with an alternative sequence alignment of TSHR/LHR in which TSHR CFLANS does not separate out as a continuous uninterrupted structure.The predicted secondary structure of CFR calls for four α-helices, which likely form a compact microenvironment with CFLANS projecting into the extracellular space. The random coil structure of CFLANS allows for a likely recognition site for the putative TSHR cleaving enzyme. We suggest that following cleavage, surface protein disulfide isomerase (PDI) reduces intrachain disulfide bonds holding the A subunit (ectodomain) cleaved from the B subunit (balance of ectodomain plus signalon) together. PDI may also be involved in forming interchain disulfide bonds to yield B subunit dimers, thus enhancing signaling. The CFLANS of TSHR has deep roots in evolutionary history. It has acquired important functions in TSHR in determining receptor cleavage, the contribution to a local microenvironment that promotes redox states favorable to inter-B subunit covalent di-merization, to enhance receptor signaling. This unique chemical reaction may compensate for the relatively low numbers of TSHR molecules on thyroid cells.

Original languageEnglish
Pages (from-to)43-56
Number of pages14
JournalInternational Journal on Disability and Human Development
Issue number2
Publication statusPublished - Jan 1 2002


  • C-flanking region
  • evolution
  • leucine-rich repeats containing G protein-coupled receptors
  • sequence alignment
  • thyrotropin receptor

ASJC Scopus subject areas

  • Rehabilitation
  • Sensory Systems
  • Geriatrics and Gerontology
  • Psychiatry and Mental health
  • Advanced and Specialised Nursing
  • Speech and Hearing

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