Summary: START domain

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Wikipedia: StAR-related transfer domain
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StAR-related transfer domain Edit Wikipedia article

START domain

Identifiers

Symbol

START

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

START

star-related lipid transport domain of mln64

Identifiers

Symbol

START

Pfam clan

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

START (StAR-related lipid-transfer) is a lipid-binding domain in StAR, HD-ZIP and signalling proteins.^[1] The archetypical domain is found in StAR (Steroidogenic acute regulatory protein), a mitochondrial protein that is synthesized in steroid-producing cells.^[2] 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.^[3]

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.^[1]^[4]

Structure[edit]

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.^[5] 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.^[4]^[5]

Human proteins containing the START domain[edit]

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[edit]

These proteins are primarily concerned with cholesterol transport

StAR (STARD1)

MLN64 (STARD3)

StarD4 subfamily[edit]

These proteins are involved in cholesterol and oxysterol transport

STARD4

STARD5

STARD6

Phospholipid/sphingolipid binding StarD2 subfamily[edit]

PCTP (STARD2)

STARD7

STARD10

COL4A3BP (STARD11)

SAM-RhoGAP-START subfamily[edit]

These proteins contain both the START domain and Rho-GTPase signaling activity

STARD8 (DLC-3)

DLC1 (STARD12)

STARD13 (DLC-2)

Acyl-CoA thioesterase subfamily[edit]

The members of this subfamily possess the START domain and thioesterase activity

ACOT11 (STARD14)

ACOT12 (STARD15)

References[edit]

^ ^a ^b 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.
^ ^a ^b 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.
^ ^a ^b 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.

This article incorporates text from the public domain Pfam and InterPro IPR002913

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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START domain Provide feedback

No Pfam abstract.

Literature references

Ponting CP, Aravind L; , Trends Biochem Sci 1999;24:130-132.: START: a lipid-binding domain in StAR, HD-ZIP and signalling proteins. PUBMED:10322415 EPMC:10322415

Internal database links

Similarity to PfamA using HHSearch:

DUF3074

External database links

PANDIT:	PF01852
Pseudofam:	PF01852
SCOP:	1em2
SMART:	START
SYSTERS:	START

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].

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 Bet_V_1_like (CL0209), which has the following description:

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 [1][2][3] 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

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 using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.

Alignment types

We make a range of alignments for each Pfam-A family:

seed: the curated alignment from which the HMM for the family is built
full: the alignment generated by searching the sequence database using the HMM
RP15/RP35/RP55/RP75: Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
NCBI: alignment generated by searching the NCBI sequence database using the family HMM
meta: alignment generated by searching the metagenomics sequence database using the family HMM

Viewing

You can see the alignments as HTML or in three different sequence viewers:

jalview: a Java applet developed at the University of Dundee. You will need Java installed before running jalview
HTML: an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
PP/Heatmap: an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
Pfam viewer: an HTML-based viewer that uses DAS to retrieve alignment fragments on request

Reformatting

You can download (or view in your browser) a text representation of a Pfam alignment in various formats:

Selex
Stockholm
FASTA
MSF

You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.

Downloading

You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.

View options

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 (18)	Full (2507)	Representative proteomes				NCBI (2394)	Meta (50)
	Seed (18)	Full (2507)	RP15 (408)	RP35 (676)	RP55 (997)	RP75 (1330)	NCBI (2394)	Meta (50)
Jalview	View	View	View	View	View	View	View	View
HTML	View	View	View	View	View	View
PP/heatmap	₁	View	View	View	View	View
Pfam viewer	View	View

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

Key: available, not generated, — not available.

Format an alignment

	Seed (18)	Full (2507)	Representative proteomes				NCBI (2394)	Meta (50)
	Seed (18)	Full (2507)	RP15 (408)	RP35 (676)	RP55 (997)	RP75 (1330)	NCBI (2394)	Meta (50)
Alignment:
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

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 (18)	Full (2507)	Representative proteomes				NCBI (2394)	Meta (50)
	Seed (18)	Full (2507)	RP15 (408)	RP35 (676)	RP55 (997)	RP75 (1330)	NCBI (2394)	Meta (50)
Raw Stockholm	Download	Download	Download	Download	Download	Download	Download	Download
Gzipped	Download	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.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

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

Seed source:

Alignment kindly provided by SMART

Previous IDs:

none

Type:

Domain

Author:

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 information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	20.6	20.6
Trusted cut-off	20.7	20.6
Noise cut-off	20.5	20.5

Model length:

206

Family (HMM) version:

14

Download:

download the raw HMM for this family

Species distribution

Sunburst
Tree

Sunburst controls

Show

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...

This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.

How the sunburst is generated

The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.

In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:

superkingdom
kingdom
phylum
class
order
family
genus
species

Colouring and labels

Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.

As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.

Anomalies in the taxonomy tree

There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.

Missing taxonomic levels

Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.

Unmapped species names

The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.

So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".

Sub-species

Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.

Too many species/sequences

For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.

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Tree controls

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The tree shows the occurrence of this domain across different species. More...

Species trees

We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.

Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.

If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.

Interactive tree

For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.

We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.

Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.

We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.

You can use the tree controls to manipulate how the interactive tree is displayed:

show/hide the summary boxes
highlight species that are represented in the seed alignment
expand/collapse the tree or expand it to a given depth
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Interactions

There is 1 interaction for this family. More...

START

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 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.

Loading structure mapping...

Archea	Eukaryota
Bacteria	Other sequences
Viruses	Unclassified
Viroids	Unclassified sequence

Family: START (PF01852)

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Summary: START domain

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StAR-related transfer domain Edit Wikipedia article

Contents

Structure[edit]

Human proteins containing the START domain[edit]

Cholesterol/oxysterol binding StarD1/D3 subfamily[edit]

StarD4 subfamily[edit]

Phospholipid/sphingolipid binding StarD2 subfamily[edit]

SAM-RhoGAP-START subfamily[edit]

Acyl-CoA thioesterase subfamily[edit]

See also[edit]

References[edit]

START domain Provide feedback

Literature references

Internal database links

External database links

InterPro entry IPR002913

Domain organisation

Pfam Clan

Alignments

Alignment types

Viewing

Reformatting

Downloading

View options

Format an alignment

Download options

External links

HMM logo

Trees

Curation and family details

Curation

HMM information

Species distribution

Sunburst controls

Weight segments by...

Change the size of the sunburst

Colour assignments

Selections

Currently selected:

How the sunburst is generated

Colouring and labels

Anomalies in the taxonomy tree

Missing taxonomic levels

Unmapped species names

Sub-species

Too many species/sequences

Tree controls

Annotation

Download tree

Selected sequences

Species trees

Interactive tree

Interactions

Structures