Limits...
The complex binding mode of the peptide hormone H2 relaxin to its receptor RXFP1.

Sethi A, Bruell S, Patil N, Hossain MA, Scott DJ, Petrie EJ, Bathgate RA, Gooley PR - Nat Commun (2016)

Bottom Line: H2 relaxin is hypothesized to bind with high affinity to the LRR domain enabling the LDLa module to bind and activate the transmembrane domain of RXFP1.Here we define a relaxin-binding site on the LDLa-LRR linker, essential for the high affinity of H2 relaxin for the ectodomain of RXFP1, and show that residues within the LDLa-LRR linker are critical for receptor activation.We propose H2 relaxin binds and stabilizes a helical conformation of the LDLa-LRR linker that positions residues of both the linker and the LDLa module to bind the transmembrane domain and activate RXFP1.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry &Molecular Biology, The University of Melbourne, Victoria 3010, Australia.

ABSTRACT
H2 relaxin activates the relaxin family peptide receptor-1 (RXFP1), a class A G-protein coupled receptor, by a poorly understood mechanism. The ectodomain of RXFP1 comprises an N-terminal LDLa module, essential for activation, tethered to a leucine-rich repeat (LRR) domain by a 32-residue linker. H2 relaxin is hypothesized to bind with high affinity to the LRR domain enabling the LDLa module to bind and activate the transmembrane domain of RXFP1. Here we define a relaxin-binding site on the LDLa-LRR linker, essential for the high affinity of H2 relaxin for the ectodomain of RXFP1, and show that residues within the LDLa-LRR linker are critical for receptor activation. We propose H2 relaxin binds and stabilizes a helical conformation of the LDLa-LRR linker that positions residues of both the linker and the LDLa module to bind the transmembrane domain and activate RXFP1.

No MeSH data available.


Sequence alignment of the LDLa-linker and domain structure of RXFP1.(a) Alignment of the sequences of the LDLa module and the 32-residue linker connecting to the LRR domain. Organisms shown human, rhesus (Macaca mulatta), Gibbon (Nomascus leucogenys), Orangutan (Pongo abelii), Horse (Equus caballus), Mouse (Mus musculus), Rat (Rattus norvegicus), Shrew (Tree Shrew; Tupaia belangeri), Dolphin (Tursiops truncatus) and Wallaby (Macropus eugenii). Sequences are from Genebank. (b) Model of the domain structure of RXFP1 showing the known structure of the N-terminal LDLa module (cyan) (pdb 2jm4) and homology models of the LRR (blue) and TM (orange) domains connected by linkers of unknown structure.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4837482&req=5

f1: Sequence alignment of the LDLa-linker and domain structure of RXFP1.(a) Alignment of the sequences of the LDLa module and the 32-residue linker connecting to the LRR domain. Organisms shown human, rhesus (Macaca mulatta), Gibbon (Nomascus leucogenys), Orangutan (Pongo abelii), Horse (Equus caballus), Mouse (Mus musculus), Rat (Rattus norvegicus), Shrew (Tree Shrew; Tupaia belangeri), Dolphin (Tursiops truncatus) and Wallaby (Macropus eugenii). Sequences are from Genebank. (b) Model of the domain structure of RXFP1 showing the known structure of the N-terminal LDLa module (cyan) (pdb 2jm4) and homology models of the LRR (blue) and TM (orange) domains connected by linkers of unknown structure.

Mentions: G-protein coupled receptors (GPCRs), the largest class of cell-surface receptors, are characterized by a transmembrane domain (TMD) of seven helices. Their activation mechanism typically involves the binding of an extracellular signalling molecule causing conformational changes within the TMD that trigger the coupling of G-proteins to activate downstream signalling1. The relaxin family peptide receptor-1 (RXFP1), is a class A GPCR that in addition to the TMD, comprises a large extracellular domain of leucine-rich repeats (LRRs) and an N-terminal low density lipoprotein class A (LDLa) module, which further classifies this receptor as a Type C leucine-rich repeat containing GPCR (LGR; Fig. 1)23. Only RXFP1 and the closely related INSL3 receptor, RXFP2, belong to this classification and they are the only type C LGRs found in mammals. Currently no other human GPCR containing LDLa modules has been reported4.


The complex binding mode of the peptide hormone H2 relaxin to its receptor RXFP1.

Sethi A, Bruell S, Patil N, Hossain MA, Scott DJ, Petrie EJ, Bathgate RA, Gooley PR - Nat Commun (2016)

Sequence alignment of the LDLa-linker and domain structure of RXFP1.(a) Alignment of the sequences of the LDLa module and the 32-residue linker connecting to the LRR domain. Organisms shown human, rhesus (Macaca mulatta), Gibbon (Nomascus leucogenys), Orangutan (Pongo abelii), Horse (Equus caballus), Mouse (Mus musculus), Rat (Rattus norvegicus), Shrew (Tree Shrew; Tupaia belangeri), Dolphin (Tursiops truncatus) and Wallaby (Macropus eugenii). Sequences are from Genebank. (b) Model of the domain structure of RXFP1 showing the known structure of the N-terminal LDLa module (cyan) (pdb 2jm4) and homology models of the LRR (blue) and TM (orange) domains connected by linkers of unknown structure.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837482&req=5

f1: Sequence alignment of the LDLa-linker and domain structure of RXFP1.(a) Alignment of the sequences of the LDLa module and the 32-residue linker connecting to the LRR domain. Organisms shown human, rhesus (Macaca mulatta), Gibbon (Nomascus leucogenys), Orangutan (Pongo abelii), Horse (Equus caballus), Mouse (Mus musculus), Rat (Rattus norvegicus), Shrew (Tree Shrew; Tupaia belangeri), Dolphin (Tursiops truncatus) and Wallaby (Macropus eugenii). Sequences are from Genebank. (b) Model of the domain structure of RXFP1 showing the known structure of the N-terminal LDLa module (cyan) (pdb 2jm4) and homology models of the LRR (blue) and TM (orange) domains connected by linkers of unknown structure.
Mentions: G-protein coupled receptors (GPCRs), the largest class of cell-surface receptors, are characterized by a transmembrane domain (TMD) of seven helices. Their activation mechanism typically involves the binding of an extracellular signalling molecule causing conformational changes within the TMD that trigger the coupling of G-proteins to activate downstream signalling1. The relaxin family peptide receptor-1 (RXFP1), is a class A GPCR that in addition to the TMD, comprises a large extracellular domain of leucine-rich repeats (LRRs) and an N-terminal low density lipoprotein class A (LDLa) module, which further classifies this receptor as a Type C leucine-rich repeat containing GPCR (LGR; Fig. 1)23. Only RXFP1 and the closely related INSL3 receptor, RXFP2, belong to this classification and they are the only type C LGRs found in mammals. Currently no other human GPCR containing LDLa modules has been reported4.

Bottom Line: H2 relaxin is hypothesized to bind with high affinity to the LRR domain enabling the LDLa module to bind and activate the transmembrane domain of RXFP1.Here we define a relaxin-binding site on the LDLa-LRR linker, essential for the high affinity of H2 relaxin for the ectodomain of RXFP1, and show that residues within the LDLa-LRR linker are critical for receptor activation.We propose H2 relaxin binds and stabilizes a helical conformation of the LDLa-LRR linker that positions residues of both the linker and the LDLa module to bind the transmembrane domain and activate RXFP1.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry &Molecular Biology, The University of Melbourne, Victoria 3010, Australia.

ABSTRACT
H2 relaxin activates the relaxin family peptide receptor-1 (RXFP1), a class A G-protein coupled receptor, by a poorly understood mechanism. The ectodomain of RXFP1 comprises an N-terminal LDLa module, essential for activation, tethered to a leucine-rich repeat (LRR) domain by a 32-residue linker. H2 relaxin is hypothesized to bind with high affinity to the LRR domain enabling the LDLa module to bind and activate the transmembrane domain of RXFP1. Here we define a relaxin-binding site on the LDLa-LRR linker, essential for the high affinity of H2 relaxin for the ectodomain of RXFP1, and show that residues within the LDLa-LRR linker are critical for receptor activation. We propose H2 relaxin binds and stabilizes a helical conformation of the LDLa-LRR linker that positions residues of both the linker and the LDLa module to bind the transmembrane domain and activate RXFP1.

No MeSH data available.