Summary: START domain
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StAR-related transfer domain Edit Wikipedia article
star-related lipid transport domain of mln64
START (StAR-related lipid-transfer) is a lipid-binding domain in StAR, HD-ZIP and signalling proteins. The archetypical domain is found in StAR (Steroidogenic acute regulatory protein), a mitochondrial protein that is synthesized in steroid-producing cells. StAR and initiates steroid production by mediating the delivery of cholesterol to the first enzyme in steroidogenic pathway. The START domain is critical for this activity, perhaps through the binding of cholesterol. Following the discovery of StAR, 15 START-domain-containing proteins (termed STARD1 through STARD15) were subsequently identified in vertebrates as well as other that are related.
Thousands of proteins containing at least one START domain have been determined in invertebrates, bacteria and plants to form a larger superfamily, variously known as START, Bet v1-like or SRPBCC (START/RHOalphaC/PITP/Bet v1/CoxG/CalC) domain proteins, all of which bind hydrophobic ligands. In the case of plants, many of the START proteins fall into the category of putative lipid/sterol-binding homeodomain (HD) transcription factors or HD-START proteins.
Representatives of the START domain family bind different substances or ligands such as sterols (e.g., StAR or STARD1) and lipids like phosphatidylcholine (phosphatidylcholine transfer protein, also called PCTP or STARD2) and have enzymatic activities. Ligand binding by the START domain in multidomain proteins can also regulate the activities of the other domains, such as the RhoGAP domain, the homeodomain and the thioesterase domain.
The crystal structure of START domain of human MLN64 shows an alpha/beta fold built around a U-shaped incomplete beta-barrel. Most importantly, the interior of the protein encompasses a 26 × 12 × 11-Angstrom hydrophobic tunnel that is apparently large enough to bind a single cholesterol molecule. The START domain structure revealed an unexpected similarity to that of the birch pollen allergen Bet v 1 and to bacterial polyketide cyclases[disambiguation needed]/aromatases.
Human proteins containing the START domain
START domain-containing proteins in the human are divided into five subfamilies. An exception is StarD9 whose activity remains unknown. Other proteins also exist in the human with domains that are members of the START-based superfamily such as PITP, but are not part of the START domain itself.
Cholesterol/oxysterol binding StarD1/D3 subfamily
These proteins are primarily concerned with cholesterol transport
- StAR (STARD1)
- MLN64 (STARD3)
These proteins are involved in cholesterol and oxysterol transport
Phospholipid/sphingolipid binding StarD2 subfamily
These proteins contain both the START domain and Rho-GTPase signaling activity
Acyl-CoA thioesterase subfamily
The members of this subfamily possess the START domain and thioesterase activity
- Ponting CP, Aravind L (1999). "START: a lipid-binding domain in StAR, HD-ZIP and signalling proteins". Trends Biochem. Sci. 24 (4): 130–132. doi:10.1016/S0968-0004(99)01362-6. PMID 10322415.
- Clark BJ, Wells J, King SR, Stocco DM (1994). "The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR)". J. Biol. Chem. 269 (45): 28314–28322. PMID 7961770.
- Schrick K, Nguyen D, Karlowski WM, Mayer KF (2004). "START lipid/sterol-binding domains are amplified in plants and are predominantly associated with homeodomain transcription factors". Genome Biol. 5: R41. doi:10.1186/gb-2004-5-6-r41. PMC 463074. PMID 15186492.
- Koonin EV, Aravind L, Iyer LM (2001). "Adaptations of the helix-grip fold for ligand binding and catalysis in the START domain superfamily". Proteins 43 (2): 134–144. doi:10.1002/1097-0134(20010501)43:2<134::AID-PROT1025>3.0.CO;2-I. PMID 11276083.
- Hurley JH, Tsujishita Y (2000). "Structure and lipid transport mechanism of a StAR-related domain". Nat. Struct. Biol. 7 (5): 408–414. doi:10.1038/75192. PMID 10802740.
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Internal database links
|Similarity to PfamA using HHSearch:||DUF3074|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR002913
START (StAR-related lipid-transfer) is a lipid-binding domain in StAR, HD-ZIP and signalling proteins [PUBMED:10322415]. StAR (Steroidogenic Acute Regulatory protein) is a mitochondrial protein that is synthesised in response to luteinising hormone stimulation [PUBMED:7961770]. Expression of the protein in the absence of hormone stimulation is sufficient to induce steroid production, suggesting that this protein is required in the acute regulation of steroidogenesis. Representatives of the START domain family have been shown to bind different ligands such as sterols (StAR protein) and phosphatidylcholine (PC-TP). Ligand binding by the START domain can also regulate the activities of other domains that co-occur with the START domain in multidomain proteins such as Rho-gap, the homeodomain, and the thioesterase domain [PUBMED:10322415, PUBMED:11276083].
The crystal structure of START domain of human MLN64 shows an alpha/beta fold built around an U-shaped incomplete beta-barrel. Most importantly, the interior of the protein encompasses a 26 x 12 x 11 Angstroms hydrophobic tunnel that is apparently large enough to bind a single cholesterol molecule [PUBMED:10802740]. The START domain structure revealed an unexpected similarity to that of the birch pollen allergen Bet v 1 and to bacterial polyketide cyclases/aromatases [PUBMED:11276083, PUBMED:10802740].
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The Bet_V_I family is composed of sequences related to the major Birch (Betula verrucose) pollen antigen Betv1. This allergen is known to cause hayfever, dermatitis, asthma and occasionally anaphylactic shock. The other families in this clan share the same structure as Betv1 which is composed of antiparallel beta sheets and alpha helices. There is a cavity between the beta sheet and a long C terminal helix. The cavity appears to play roles in the binding of lipid molecules  which seems a common feature of the families in this clan.
The clan contains the following 14 members:AHSA1 Aromatic_hydrox Bet_v_1 COXG DUF1857 DUF2505 DUF3074 DUF3211 DUF3284 IP_trans Polyketide_cyc Polyketide_cyc2 Ring_hydroxyl_A START
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Curation and family details
|Seed source:||Alignment kindly provided by SMART|
|Number in seed:||18|
|Number in full:||2507|
|Average length of the domain:||186.50 aa|
|Average identity of full alignment:||16 %|
|Average coverage of the sequence by the domain:||33.31 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||14|
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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 START domain has been found. There are 40 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 seqence.
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