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In a Class of Their Own - RXFP1 and RXFP2 are Unique Members of the LGR Family.

Petrie EJ, Lagaida S, Sethi A, Bathgate RA, Gooley PR - Front Endocrinol (Lausanne) (2015)

Bottom Line: In the LGRs, the ECD binds the hormone or ligand, usually through the LRRs, that ultimately results in activation and signaling.While the LDLa module is essential for activation of the type C LGRs, the molecular mechanism for this process is unknown.Experimental data for the potential interactions of the type C LGR ligands with the LRR domain, the transmembrane domain, and the LDLa module are summarized.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne , Parkville, VIC , Australia ; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Parkville, VIC , Australia.

ABSTRACT
The leucine-rich repeat-containing G protein-coupled receptors (LGRs) family consists of three groups: types A, B, and C and all contain a large extracellular domain (ECD) made up of the structural motif - the leucine-rich repeat (LRR). In the LGRs, the ECD binds the hormone or ligand, usually through the LRRs, that ultimately results in activation and signaling. Structures are available for the ECD of type A and B LGRs, but not the type C LGRs. This review discusses the structural features of LRR proteins, and describes the known structures of the type A and B LGRs and predictions that can be made for the type C LGRs. The mechanism of activation of the LGRs is discussed with a focus on the role of the low-density lipoprotein class A (LDLa) module, a unique feature of the type C LGRs. While the LDLa module is essential for activation of the type C LGRs, the molecular mechanism for this process is unknown. Experimental data for the potential interactions of the type C LGR ligands with the LRR domain, the transmembrane domain, and the LDLa module are summarized.

No MeSH data available.


Related in: MedlinePlus

Structures of ectodomains of members of the LGR family. (A) The type A member FSHr (PBD: 4AY9) shows nine LRRs. LRR1–6 show a shallow curvature while the dominance of LP motifs in the convex side of LRR7–9 results in a steep curvature. The ligand shows interactions to most of the LRRs, especially LRR1–5 and LRR7–9 (B) The type B member LGR4 (PDB: 4KT1). The concave side of the LRR protein is separated into two sheets, LRR1–10 and LRR11–17, due to the absence of the conserved Asn residues within the LRR motif of LRR11 and 12. The ligand binds to the first sheet, making contacts with residues in LRR1, LRR3–9. (C) A homology model of the ECD of the type C member RXFP1. The 10 LRRs are predicted to form a shallow curvature. The ligand, H2 relaxin, is expected to bind to LRR4–6 and LRR8. The structure of the N-terminal LDLa module (PDB: 2JM4) for this ECD is also shown, although the structure of the linker that joins to the LRR domain remains unknown. In each structure, additional β-strands (red), which are integral to the domain, are shown but these strands typically lack the xLx portion of the LRR motif, and usually include disulfide bonds characteristic of the N- and C-terminal capping motifs. At the N-terminal end of each LRR domain, an antiparallel β-strand followed by a β-strand parallel to the remainder of the LRR is observed. At the C-terminal end, significant differences for the three members are observed. For FSHr, a large hinge containing a functionally important sulfated Tyr residue is present; for LGR4, this hinge is absent, but a typical CF3 capping motif is present; for RXFP1, the C-terminal cap does not appear conserved, the hinge is short, and therefore, the structure of this region is difficult to predict.
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Figure 1: Structures of ectodomains of members of the LGR family. (A) The type A member FSHr (PBD: 4AY9) shows nine LRRs. LRR1–6 show a shallow curvature while the dominance of LP motifs in the convex side of LRR7–9 results in a steep curvature. The ligand shows interactions to most of the LRRs, especially LRR1–5 and LRR7–9 (B) The type B member LGR4 (PDB: 4KT1). The concave side of the LRR protein is separated into two sheets, LRR1–10 and LRR11–17, due to the absence of the conserved Asn residues within the LRR motif of LRR11 and 12. The ligand binds to the first sheet, making contacts with residues in LRR1, LRR3–9. (C) A homology model of the ECD of the type C member RXFP1. The 10 LRRs are predicted to form a shallow curvature. The ligand, H2 relaxin, is expected to bind to LRR4–6 and LRR8. The structure of the N-terminal LDLa module (PDB: 2JM4) for this ECD is also shown, although the structure of the linker that joins to the LRR domain remains unknown. In each structure, additional β-strands (red), which are integral to the domain, are shown but these strands typically lack the xLx portion of the LRR motif, and usually include disulfide bonds characteristic of the N- and C-terminal capping motifs. At the N-terminal end of each LRR domain, an antiparallel β-strand followed by a β-strand parallel to the remainder of the LRR is observed. At the C-terminal end, significant differences for the three members are observed. For FSHr, a large hinge containing a functionally important sulfated Tyr residue is present; for LGR4, this hinge is absent, but a typical CF3 capping motif is present; for RXFP1, the C-terminal cap does not appear conserved, the hinge is short, and therefore, the structure of this region is difficult to predict.

Mentions: The FSHr crystal structure is the best understood of the LGRs (46). The LRR domain consists of repeats of irregular length and conformation (Figure 1A). As expected the LRR domain contains an LRRNT with an antiparallel β-strand followed by the expected parallel β-strand of this cap. This is then followed by nine parallel β-strands of the LRR domain (Table 1), and additional two parallel β-strands in the C-terminal cysteine cap, which form a typical CF3 cap. Prior to the last parallel β-strand, there is an insertion of an α-helix and a long hairpin loop that contains a sulfated tyrosine, collectively referred to as the hinge region, and forms an integrated structure within the LRR domain (Figure 1A) (47). Consequently, the entire LRR domain consists of 12 parallel β-strands. On the convex side of the LRR domain, there are seven short β-strands separated into three β-sheets. Importantly, the intervening sequences of the convex side follow from the N-terminal end as: an LP motif, three AF motifs, one LP motif, two AF motifs, and then three LP motifs. Thus, there is an increasing curvature of the domain running from N- to C-terminus. Superimposing the structures of the FSHr and TSHr LRR domains shows similar structures despite different primary sequences and disulfide connectivity (40).


In a Class of Their Own - RXFP1 and RXFP2 are Unique Members of the LGR Family.

Petrie EJ, Lagaida S, Sethi A, Bathgate RA, Gooley PR - Front Endocrinol (Lausanne) (2015)

Structures of ectodomains of members of the LGR family. (A) The type A member FSHr (PBD: 4AY9) shows nine LRRs. LRR1–6 show a shallow curvature while the dominance of LP motifs in the convex side of LRR7–9 results in a steep curvature. The ligand shows interactions to most of the LRRs, especially LRR1–5 and LRR7–9 (B) The type B member LGR4 (PDB: 4KT1). The concave side of the LRR protein is separated into two sheets, LRR1–10 and LRR11–17, due to the absence of the conserved Asn residues within the LRR motif of LRR11 and 12. The ligand binds to the first sheet, making contacts with residues in LRR1, LRR3–9. (C) A homology model of the ECD of the type C member RXFP1. The 10 LRRs are predicted to form a shallow curvature. The ligand, H2 relaxin, is expected to bind to LRR4–6 and LRR8. The structure of the N-terminal LDLa module (PDB: 2JM4) for this ECD is also shown, although the structure of the linker that joins to the LRR domain remains unknown. In each structure, additional β-strands (red), which are integral to the domain, are shown but these strands typically lack the xLx portion of the LRR motif, and usually include disulfide bonds characteristic of the N- and C-terminal capping motifs. At the N-terminal end of each LRR domain, an antiparallel β-strand followed by a β-strand parallel to the remainder of the LRR is observed. At the C-terminal end, significant differences for the three members are observed. For FSHr, a large hinge containing a functionally important sulfated Tyr residue is present; for LGR4, this hinge is absent, but a typical CF3 capping motif is present; for RXFP1, the C-terminal cap does not appear conserved, the hinge is short, and therefore, the structure of this region is difficult to predict.
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Related In: Results  -  Collection

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Figure 1: Structures of ectodomains of members of the LGR family. (A) The type A member FSHr (PBD: 4AY9) shows nine LRRs. LRR1–6 show a shallow curvature while the dominance of LP motifs in the convex side of LRR7–9 results in a steep curvature. The ligand shows interactions to most of the LRRs, especially LRR1–5 and LRR7–9 (B) The type B member LGR4 (PDB: 4KT1). The concave side of the LRR protein is separated into two sheets, LRR1–10 and LRR11–17, due to the absence of the conserved Asn residues within the LRR motif of LRR11 and 12. The ligand binds to the first sheet, making contacts with residues in LRR1, LRR3–9. (C) A homology model of the ECD of the type C member RXFP1. The 10 LRRs are predicted to form a shallow curvature. The ligand, H2 relaxin, is expected to bind to LRR4–6 and LRR8. The structure of the N-terminal LDLa module (PDB: 2JM4) for this ECD is also shown, although the structure of the linker that joins to the LRR domain remains unknown. In each structure, additional β-strands (red), which are integral to the domain, are shown but these strands typically lack the xLx portion of the LRR motif, and usually include disulfide bonds characteristic of the N- and C-terminal capping motifs. At the N-terminal end of each LRR domain, an antiparallel β-strand followed by a β-strand parallel to the remainder of the LRR is observed. At the C-terminal end, significant differences for the three members are observed. For FSHr, a large hinge containing a functionally important sulfated Tyr residue is present; for LGR4, this hinge is absent, but a typical CF3 capping motif is present; for RXFP1, the C-terminal cap does not appear conserved, the hinge is short, and therefore, the structure of this region is difficult to predict.
Mentions: The FSHr crystal structure is the best understood of the LGRs (46). The LRR domain consists of repeats of irregular length and conformation (Figure 1A). As expected the LRR domain contains an LRRNT with an antiparallel β-strand followed by the expected parallel β-strand of this cap. This is then followed by nine parallel β-strands of the LRR domain (Table 1), and additional two parallel β-strands in the C-terminal cysteine cap, which form a typical CF3 cap. Prior to the last parallel β-strand, there is an insertion of an α-helix and a long hairpin loop that contains a sulfated tyrosine, collectively referred to as the hinge region, and forms an integrated structure within the LRR domain (Figure 1A) (47). Consequently, the entire LRR domain consists of 12 parallel β-strands. On the convex side of the LRR domain, there are seven short β-strands separated into three β-sheets. Importantly, the intervening sequences of the convex side follow from the N-terminal end as: an LP motif, three AF motifs, one LP motif, two AF motifs, and then three LP motifs. Thus, there is an increasing curvature of the domain running from N- to C-terminus. Superimposing the structures of the FSHr and TSHr LRR domains shows similar structures despite different primary sequences and disulfide connectivity (40).

Bottom Line: In the LGRs, the ECD binds the hormone or ligand, usually through the LRRs, that ultimately results in activation and signaling.While the LDLa module is essential for activation of the type C LGRs, the molecular mechanism for this process is unknown.Experimental data for the potential interactions of the type C LGR ligands with the LRR domain, the transmembrane domain, and the LDLa module are summarized.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, University of Melbourne , Parkville, VIC , Australia ; Bio21 Molecular Science and Biotechnology Institute, University of Melbourne , Parkville, VIC , Australia.

ABSTRACT
The leucine-rich repeat-containing G protein-coupled receptors (LGRs) family consists of three groups: types A, B, and C and all contain a large extracellular domain (ECD) made up of the structural motif - the leucine-rich repeat (LRR). In the LGRs, the ECD binds the hormone or ligand, usually through the LRRs, that ultimately results in activation and signaling. Structures are available for the ECD of type A and B LGRs, but not the type C LGRs. This review discusses the structural features of LRR proteins, and describes the known structures of the type A and B LGRs and predictions that can be made for the type C LGRs. The mechanism of activation of the LGRs is discussed with a focus on the role of the low-density lipoprotein class A (LDLa) module, a unique feature of the type C LGRs. While the LDLa module is essential for activation of the type C LGRs, the molecular mechanism for this process is unknown. Experimental data for the potential interactions of the type C LGR ligands with the LRR domain, the transmembrane domain, and the LDLa module are summarized.

No MeSH data available.


Related in: MedlinePlus