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8  structures 523  species 0  interactions 17360  sequences 1075  architectures

Family: GPS (PF01825)

Summary: GPCR proteolysis site, GPS, motif

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GPCR proteolysis site, GPS, motif Provide feedback

The GPS motif is found in GPCRs, and is the site for auto-proteolysis, so is thus named, GPS [1,2,3,4]. The GPS motif is a conserved sequence of ~40 amino acids containing canonical cysteine and tryptophan residues, and is the most highly conserved part of the domain. In most, if not all, cell-adhesion GPCRs these undergo autoproteolysis in the GPS between a conserved aliphatic residue (usually a leucine) and a threonine, serine, or cysteine residue [5]. In higher eukaryotes this motif is found embedded in the C-terminal beta-stranded part of a GAIN domain - GPCR-Autoproteolysis INducing (GAIN). The GAIN-GPS domain adopts a fold in which the GPS motif, at the C-terminus, forms five beta-strands that are tightly integrated into the overall GAIN domain. The GPS motif, evolutionarily conserved from tetrahymena to mammals, is the only extracellular domain shared by all human cell-adhesion GPCRs and PKD proteins, and is the locus of multiple human disease mutations. The GAIN-GPS domain is both necessary and sufficient functionally for autoproteolysis, suggesting an autoproteolytic mechanism whereby the overall GAIN domain fine-tunes the chemical environment in the GPS to catalyse peptide bond hydrolysis [6]. In the cell-adhesion GPCRs and PKD proteins, the GPS motif is always located at the end of their long N-terminal extracellular regions, immediately before the first transmembrane helix of the respective protein.

Literature references

  1. Krasnoperov V, Bittner MA, Holz RW, Chepurny O, Petrenko AG; , J Biol Chem 1999;274:3590-3596.: Structural requirements for alpha-latrotoxin binding and alpha- latrotoxin-stimulated secretion. A study with calcium-independent receptor of alpha-latrotoxin (CIRL) deletion mutants. PUBMED:9920906 EPMC:9920906

  2. Sugita S, Ichtchenko K, Khvotchev M, Sudhof TC; , J Biol Chem 1998;273:32715-32724.: alpha-Latrotoxin receptor CIRL/latrophilin 1 (CL1) defines an unusual family of ubiquitous G-protein-linked receptors. G-protein coupling not required for triggering exocytosis. PUBMED:9830014 EPMC:9830014

  3. Ponting CP, Hofmann K, Bork P; , Curr Biol 1999;26:585-588.: A latrophilin/CL-1-like GPS domain in polycystin-1. PUBMED:10469603 EPMC:10469603

  4. Wei W, Hackmann K, Xu H, Germino G, Qian F; , J Biol Chem. 2007;282:21729-21737.: Characterization of cis-autoproteolysis of polycystin-1, the product of human polycystic kidney disease 1 gene. PUBMED:17525154 EPMC:17525154

  5. Krasnoperov V, Lu Y, Buryanovsky L, Neubert TA, Ichtchenko K, Petrenko AG;, J Biol Chem. 2002;277:46518-46526.: Post-translational proteolytic processing of the calcium-independent receptor of alpha-latrotoxin (CIRL), a natural chimera of the cell adhesion protein and the G protein-coupled receptor. Role of the G protein-coupled receptor proteolysis site (GPS) motif. PUBMED:12270923 EPMC:12270923

  6. Arac D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Sudhof TC, Brunger AT;, EMBO J. 2012;31:1364-1378.: A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. PUBMED:22333914 EPMC:22333914

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000203

GPS (for GPCR proteolytic site) motif is found in a number of G-protein-coupled receptors (GPCRs) including CIRLs/latrophilins and in other membrane-associated proteins like the sea urchin receptor for egg jelly protein (REJ) [ PUBMED:10469603 ].

For the CIRL-1, CIRL-2, CIRL-3 and CD-97 proteins, it has been shown that they are each made of two non-covalently bound subunits resulting from the endogenous proteolytic cleavage of a precursor protein. Because the cysteine-rich domain of CIRL-1 and possibly other receptors is involved in the endogenous proteolytic processing of CIRL-1 and possibly other receptors, it has been named GPS for GPCR proteolytic site. As the amino acids surrounding the putative cleavage site are the most conserved residues in the GPS domain, it has been suggested that all proteins containing it may be cleaved at this position [ PUBMED:10026162 , PUBMED:9830014 , PUBMED:10469603 ].

GPS motifs are about 50 residues long and contain either 2 or 4 cysteine residues that are likely to form disulphide bridges. Based on conservation of these cysteines the following pairing can be predicted.

                             |                 |
           +-----------------+---------------+ |
           |                 |               | |
                                                   cleavage site

The GPS motif is an integral part of a much larger (320-residue approximately) domain that has been termed GPCR-Autoproteolysis INducing (GAIN) domain. The GAIN domain represents an autoproteolytic fold whose function is likely relevant for GPCR signalling [ PUBMED:22333914 ].

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Gain (CL0661), which has the following description:

Members of this clan belong to GAIN domain with an autoproteolytic motif. The G-protein-coupled receptor (GPCR) autoproteolysis-inducing (GAIN) domain, includes GPCRs involved in adhesion with a characteristic autoproteolysis motif of HLT/S known as the GPCR proteolysis site (GPS). GPS is also shared by polycystic kidney disease (PKD) proteins. GAIN has been shown to be both necessary and sufficient for autoproteolysis [1].

The clan contains the following 6 members:

DUF1191 GAIN GPS Nucleoporin2 UPF0560 ZU5


We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets and the UniProtKB sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

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HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: SMART
Previous IDs: GPS; GAIN; GAIN-GPS;
Type: Motif
Sequence Ontology: SO:0001067
Author: Bateman A
Number in seed: 295
Number in full: 17360
Average length of the domain: 44.2 aa
Average identity of full alignment: 39 %
Average coverage of the sequence by the domain: 3.39 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 22.5 22.5
Trusted cut-off 22.5 22.5
Noise cut-off 22.4 22.4
Model length: 44
Family (HMM) version: 24
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the GPS domain has been found. There are 8 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A044R2Y8 View 3D Structure Click here
A0A077YXA3 View 3D Structure Click here
A0A077ZFL1 View 3D Structure Click here
A0A096MKI0 View 3D Structure Click here
A0A0G2JSI4 View 3D Structure Click here
A0A0G2JSN6 View 3D Structure Click here
A0A0G2JST1 View 3D Structure Click here
A0A0G2JSU2 View 3D Structure Click here
A0A0G2K4Q7 View 3D Structure Click here
A0A0G2K538 View 3D Structure Click here
A0A0K0E616 View 3D Structure Click here
A0A0N4UN70 View 3D Structure Click here
A0A0R4IAT2 View 3D Structure Click here
A0A140LGW6 View 3D Structure Click here
A0A2R8PX08 View 3D Structure Click here
A0A2R8Q3H9 View 3D Structure Click here
A0A2R8Q5D8 View 3D Structure Click here
A0A2R8Q5E7 View 3D Structure Click here
A0A2R8Q5E9 View 3D Structure Click here
A0A2R8QJ82 View 3D Structure Click here
A0A2R8QKH4 View 3D Structure Click here
A0A2R8QM07 View 3D Structure Click here
A0A2R8QMH5 View 3D Structure Click here
A0A2R8QN46 View 3D Structure Click here
A0A3P7E588 View 3D Structure Click here
A0A3P7F9U6 View 3D Structure Click here
A0A5S6PD74 View 3D Structure Click here
A0A5S6PF64 View 3D Structure Click here
A0A5S6PFF2 View 3D Structure Click here
A1Z7G7 View 3D Structure Click here
A6QLU6 View 3D Structure Click here
B3MFV7 View 3D Structure Click here
B4GD14 View 3D Structure Click here
B4HS00 View 3D Structure Click here
B4J780 View 3D Structure Click here
B4KMZ1 View 3D Structure Click here
B4LNA8 View 3D Structure Click here
C0HL12 View 3D Structure Click here
C6KFA3 View 3D Structure Click here
D3ZF17 View 3D Structure Click here