Summary: Sterol-sensing domain of SREBP cleavage-activation
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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
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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
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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
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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
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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
SCOOP: | ACR_tran MMPL Patched SecD_SecF |
Similarity to PfamA using HHSearch: | Patched MMPL |
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-sensingAlignments
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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Seed (22) |
Full (5711) |
Representative proteomes | UniProt (9556) |
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RP15 (896) |
RP35 (2042) |
RP55 (4214) |
RP75 (5754) |
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PP/heatmap | 1 |
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
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Seed (22) |
Full (5711) |
Representative proteomes | UniProt (9556) |
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RP15 (896) |
RP35 (2042) |
RP55 (4214) |
RP75 (5754) |
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Raw Stockholm | |||||||
Gzipped |
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...
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.
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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
Seed source: | Wood V |
Previous IDs: | SREBP-CAP_SSD; |
Type: | Family |
Sequence Ontology: | SO:0100021 |
Author: |
Wood V |
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
HMM build commands: |
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
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Model details: |
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Model length: | 153 | ||||||||||||
Family (HMM) version: | 11 | ||||||||||||
Download: | download the raw HMM for this family |
Species distribution
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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.