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46  structures 1319  species 0  interactions 5711  sequences 109  architectures

Family: Sterol-sensing (PF12349)

Summary: Sterol-sensing domain of SREBP cleavage-activation

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The Pfam group coordinates the annotation of Pfam families in Wikipedia, but we have not yet assigned a Wikipedia article to this family. If you think that a particular Wikipedia article provides good annotation, please let us know.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Sterol-sensing domain of SREBP cleavage-activation Provide feedback

Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that promote lipid synthesis in animal cells. They are embedded in the membranes of the endoplasmic reticulum (ER) in a helical hairpin orientation and are released from the ER by a two-step proteolytic process. Proteolysis begins when the SREBPs are cleaved at Site-1, which is located at a leucine residue in the middle of the hydrophobic loop in the lumen of the ER [1]. Upon proteolytic processing SREBP can activate the expression of genes involved in cholesterol biosynthesis and uptake. SCAP stimulates cleavage of SREBPs via fusion of the their two C-termini [2]. This domain is the transmembrane region that traverses the membrane eight times and is the sterol-sensing domain of the cleavage protein [4]. WD40 domains are found towards the C-terminus.

Literature references

  1. Sakai J, Nohturfft A, Goldstein JL, Brown MS;, J Biol Chem. 1998;273:5785-5793.: Cleavage of sterol regulatory element-binding proteins (SREBPs) at site-1 requires interaction with SREBP cleavage-activating protein. Evidence from in vivo competition studies. PUBMED:9488713 EPMC:9488713

  2. Colgan SM, Tang D, Werstuck GH, Austin RC;, Int J Biochem Cell Biol. 2007;39:1843-1851.: Endoplasmic reticulum stress causes the activation of sterol regulatory element binding protein-2. PUBMED:17604677 EPMC:17604677

  3. Sakai J, Nohturfft A, Cheng D, Ho YK, Brown MS, Goldstein JL;, J Biol Chem. 1997;272:20213-20221.: Identification of complexes between the COOH-terminal domains of sterol regulatory element-binding proteins (SREBPs) and SREBP cleavage-activating protein. PUBMED:9242699 EPMC:9242699

  4. Yabe D, Xia ZP, Adams CM, Rawson RB;, Proc Natl Acad Sci U S A. 2002;99:16672-16677.: Three mutations in sterol-sensing domain of SCAP block interaction with insig and render SREBP cleavage insensitive to sterols. PUBMED:12482938 EPMC:12482938


Internal database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000731

The sterol-sensing domain (SSD) is an around 180 residues long cluster of five membrane-spanning segments. The SSD domain is conserved across phyla and confers sensitivity to regulation by sterol. Although the SSD domain appears to function as a regulatory domain involved in linking vesicle trafficking and protein localization with such varied processes as cholesterol homeostasis, cell signalling and cytokinesis, its exact mode of action is not clear. It is not known whether it interacts with sterols, such as cholesterol, or whether it interacts with another-sterol regulated protein. Alternatively, the SSD may interact with lipids other than cholesterol [ PUBMED:9642295 , PUBMED:10821832 , PUBMED:11932020 ].

In addition to the proteins above, the SSD is also found in a number of bacterial drug resistance proteins.

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 RND_permease (CL0322), which has the following description:

Different members of the RND superfamily have been shown to transport hydrophobic drugs, fatty acids, bile salts, organic solvents, heavy metals, autoinducers and lipooligosaccharides in bacteria [1].

The clan contains the following 5 members:

ACR_tran MMPL Patched SecD_SecF Sterol-sensing

Alignments

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.

  Seed
(22)
Full
(5711)
Representative proteomes UniProt
(9556)
RP15
(896)
RP35
(2042)
RP55
(4214)
RP75
(5754)
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HTML View             
PP/heatmap 1            

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(22)
Full
(5711)
Representative proteomes UniProt
(9556)
RP15
(896)
RP35
(2042)
RP55
(4214)
RP75
(5754)
Alignment:
Format:
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Sequence:
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Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

  Seed
(22)
Full
(5711)
Representative proteomes UniProt
(9556)
RP15
(896)
RP35
(2042)
RP55
(4214)
RP75
(5754)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download  

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

HMM logo

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...

Trees

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.

Note: You can also download the data file for the tree.

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: Wood V
Previous IDs: SREBP-CAP_SSD;
Type: Family
Sequence Ontology: SO:0100021
Author: Wood V , Coggill P
Number in seed: 22
Number in full: 5711
Average length of the domain: 148 aa
Average identity of full alignment: 27 %
Average coverage of the sequence by the domain: 12.98 %

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 22.3 22.3
Trusted cut-off 22.3 22.3
Noise cut-off 22.2 22.2
Model length: 153
Family (HMM) version: 11
Download: download the raw HMM for this family

Species distribution

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Archea Archea Eukaryota Eukaryota
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Viroids Viroids Unclassified sequence Unclassified sequence

Selections

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Structures

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 Sterol-sensing domain has been found. There are 46 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
A0A044RFS2 View 3D Structure Click here
A0A077YYG3 View 3D Structure Click here
A0A077Z154 View 3D Structure Click here
A0A0D2GD05 View 3D Structure Click here
A0A0D2GUF4 View 3D Structure Click here
A0A0G2KNF5 View 3D Structure Click here
A0A0K0DVU7 View 3D Structure Click here
A0A0K0EK36 View 3D Structure Click here
A0A0R4IFH5 View 3D Structure Click here
A0A158Q547 View 3D Structure Click here
A0A175W665 View 3D Structure Click here
A0A175W7B1 View 3D Structure Click here
A0A1C1CIJ8 View 3D Structure Click here
A0A1C1CLX1 View 3D Structure Click here
A0A1D6JCY5 View 3D Structure Click here
A0A1D8PD39 View 3D Structure Click here
A0A1D8PFW9 View 3D Structure Click here
A0A2R8Q2J0 View 3D Structure Click here
A0A2R8QHL5 View 3D Structure Click here
A0A3P7FK82 View 3D Structure Click here
A0A5K4F2X2 View 3D Structure Click here
A0A5K4F3D4 View 3D Structure Click here
A0A5K4FCP4 View 3D Structure Click here
A0A5S6PJP1 View 3D Structure Click here
A1Z6J2 View 3D Structure Click here
A2RRU4 View 3D Structure Click here
A6QM06 View 3D Structure Click here
A7Z064 View 3D Structure Click here
C0NBB8 View 3D Structure Click here
C1GRY4 View 3D Structure Click here
C1H4V0 View 3D Structure Click here
E9QEH6 View 3D Structure Click here
F1R8E2 View 3D Structure Click here
G3V7K5 View 3D Structure Click here
G5EEW0 View 3D Structure Click here
O15118 View 3D Structure Click here
O35595 View 3D Structure Click here
O35604 View 3D Structure Click here
O43043 View 3D Structure Click here
P04035 View 3D Structure Click here