Journal article
Chimeras of the rat and human FSH receptors (FSHRs) identify residues that permit or suppress transmembrane 6 mutation-induced constitutive activation of the FSHR via rearrangements of hydrophobic interactions between helices 6 and 7
Molecular endocrinology (Baltimore, Md.), Vol.16(8), pp.1881-1892
08/2002
DOI: 10.1210/me.2001-0199
PMID: 12145341
Abstract
Although a large number of naturally occurring activating mutations of the human LH receptor (hLHR) and human TSH receptor (hTSHR) have been identified, only one activating mutation of the human FSH receptor (hFSHR) has been found. Furthermore, mutations of several residues within the i3/transmembrane domain (TM) 6 region of the hFSHR that were done based upon known constitutively activating mutations of the human LHR were found to have no effect on hFSHR signaling. One of the hFSHR mutations examined in this context was the substitution of a highly conserved aspartate (D581) in TM6 with glycine. We show herein that although the basal activity of the rat FSHR (rFSHR) is similar to the hFSHR, mutation of the comparable residue (D580) in the rFSHR causes marked constitutive activation. Taking advantage of the high degree of amino acid identity between the rat and human FSHRs, we have used chimeras and point substitutions to determine the precise residues that suppress or permit constitutive activity by the D580/581G mutation. Thus, the simultaneous substitution of M576 in TM6 and H615 in TM7 of the hFSHR with the cognate rFSHR residues (threonine and tyrosine, respectively) now renders the hFSHR(D581G) mutant constitutively active. Conversely, the substitution of Y614 of the rFSHR with the cognate hFSHR residue (histidine) fully suppresses the constitutive activity of the rFSHR (D580G) mutant. Computer models of the human and rat FSHRs and mutants thereof were created based upon the crystal structure of rhodopsin. These models suggest that differences in hydrophobic interactions between TMs 6 and 7 of the rat and human FSHRs may account for the ability of TM6 of the rat, but not human, FSHR to adopt an active conformation as a result of the D580/581G mutation.
Details
- Title: Subtitle
- Chimeras of the rat and human FSH receptors (FSHRs) identify residues that permit or suppress transmembrane 6 mutation-induced constitutive activation of the FSHR via rearrangements of hydrophobic interactions between helices 6 and 7
- Creators
- Ya-Xiong Tao - Department of Physiology and Biophysics, The University of Iowa, Iowa City, Iowa 52242, USADario MizrachiDeborah L Segaloff
- Resource Type
- Journal article
- Publication Details
- Molecular endocrinology (Baltimore, Md.), Vol.16(8), pp.1881-1892
- DOI
- 10.1210/me.2001-0199
- PMID
- 12145341
- ISSN
- 0888-8809
- eISSN
- 1944-9917
- Grant note
- DK-07759 / NIDDK NIH HHS DK-25295 / NIDDK NIH HHS DK-07018 / NIDDK NIH HHS HD-22196 / NICHD NIH HHS
- Language
- English
- Date published
- 08/2002
- Academic Unit
- Molecular Physiology and Biophysics; Obstetrics and Gynecology
- Record Identifier
- 9984083997702771
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