There exist at least 30 human G-protein-coupled receptors with long Ser/Thr-rich N-termini

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Abstract

We report six novel members of the superfamily of human G-protein coupled receptors (GPCRs) found by searches in the human genome databases, termed GPR123, GPR124, GPR125, GPR126, GPR127, and GPR128. Phylogenetic analysis demonstrates that these are additional members of the family of GPCRs with long N-termini, previously termed EGF-7TM, LNB-7TM, B2 or LN-7TM, showing that there exist at least 30 such GPCRs in the human genome. Three of these receptors form their own phylogenetic cluster, while two other places in a cluster with the previously reported HE6 and GPR56 (TM7XN1) and one with EMR1-3. All the novel receptors have a GPS domain in their N-terminus, except GPR123, as well as long Ser/Thr rich regions forming mucin-like stalks. GPR124 and GPR125 have a leucine rich repeat (LRR), an immunoglobulin (Ig) domain, and a hormone-binding domain (HBD). The Ig domain shows similarities to motilin and titin, while the LRR domain shows similarities to LRIG1 and SLIT1-2. GPR127 has one EGF domain while GPR126 and GPR128 do not contain domains that are readily recognized in other proteins beyond the GPS domain. We found several human EST sequences for most of the receptors showing differential expression patterns, which may indicate that some of these receptors participate in central functions while others are more likely to have a role in the immune or reproductive systems.

Section snippets

Materials and methods

Identification of novel receptors. Sequences of known GPCRs from LN-7TM family (BAI1; NP_001693.1, BAI2; NP_001694.1, BAI3; NP_001695.1, CELSR1; NP_055061.1, CELSR2; NP_001399.1, CELSR3; NP_001398.1, CD97; NP_001775.1, EMR1; NP_001965.1, EMR2; NP_038475.1, EMR3; NP_115960.1, ETL; NP_071442.1, GPR97; AY140959, GPR110; AY140952, GPR111; AY140953, GPR112; AY140954, GPR113; AY140955, GPR114; AY140956, GPR115; AY140957, GPR116; AY140958, HE6 (GPR64); NP_005747.1, LEC1; NP_036434.1, LEC2; NP_055736.1

Results

We have recently published eight new LN-7TM receptors that were found through creation of Hidden Markov Models (HMM) based on previously known clan B and LN-TM7 receptors and a subsequent search of the human NCBI genome (http://www.ncbi.nlm.nih.gov). The Celera genome (http://www.celera.com) is however not searchable using HMMs. We therefore used the new sequences and the other LN-7TM sequences as baits for BLAST searches in the Celera genome. The result of the searches was six novel human

Discussion

The six novel receptors show clear overall structural and phylogenetic relationship to the LN-7TM receptors. Three of the new receptors (GPR123, GPR124, and GPR125) form a new separate cluster among the other LN-7TM receptors as shown in Fig. 1. Two of the receptors (GPR126 and GPR128) show phylogenetic relationship to HE6 and GPR56, which have been known for a few years, and three receptors that we recently described after searching the NCBI database with HMM models [10]. The sixth receptor

Acknowledgements

The studies were supported by the Swedish Research Council (VR, medicine), the Swedish Society for Medical Research (SSMF), Åke Wibergs Stiftelse, Petrus och Augusta Hedlunds Stiftelse, Svenska Läkaresällskapet, and Melacure Therapeutics AB, Uppsala, Sweden.

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