A single domain intrabody targeting the follicle-stimulating hormone receptor (FSHR) impacts FSH-induced G protein-dependent signalling
FEBS Letters(2023)
Abstract
Intracellular variable fragments from heavy-chain antibody from camelids (intra-VHH) have been successfully used as chaperones to solve the 3D structure of active G protein-coupled receptors bound to their transducers. However, their effect on signalling has been poorly explored, although they may provide a better understanding on the relationships between receptor conformation and activity. Here, we isolated and characterized iPRC1, the first intra-VHH recognizing a member of the large glycoprotein hormone receptors family, the follicle-stimulating hormone receptor (FSHR). This intra-VHH recognizes the FSHR 3rd intracellular loop and decreases cAMP production in response to FSH, without altering Gαs recruitment. Hence, iPRC1 behaves as an allosteric modulator and provides a new tool to complete structure/activity studies performed so far on this receptor.
### Competing Interest Statement
The authors have declared no competing interest.
* GPCR
: G protein-coupled receptor
FSH
: Follicle-stimulating hormone
FSHR
: FSH receptor
LHCGR
: Luteinizing hormone/choriogonadotropin receptor
TSHR
: Thyroid-stimulating hormone
BSA
: Bovine serum albumin
BRET
: Bioluminescence resonance energy transfer
HTRF
: Homogeneous time-resolved fluorescence
ICL
: intracellular loop
AVP
: Arginine-vasopressin
AVPR2
: Arginine-vasopressin 2 receptor
ISO
: Isoproterenol hydrochloride
ADRB2
: β2 adrenergic receptor
Fsk
: Forskolin
PBS
: Phosphate-buffered saline
RLuc8
: luciferase from the sea pansy Renilla reniformis
mGs
: Mini Gs protein, minimal engineered GTPase domain of the Gα subunit
APC
: Allophycocyanine
HEK293
: Human Embryonic Kidney 293
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