StAR-related transfer domain

Last updated
START
PDB 1em2 EBI.jpg
star-related lipid transport domain of mln64
Identifiers
SymbolSTART
Pfam PF01852
Pfam clan CL0209
InterPro IPR002913
SMART START
SCOP2 1em2 / SCOPe / SUPFAM
OPM superfamily 138
OPM protein 1ln1
Membranome 564
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
START domain
Identifiers
SymbolSTART
Pfam PF01852
InterPro IPR002913
SMART START
SCOP2 1em2 / SCOPe / SUPFAM
TCDB 9.B.64
CDD cd00177
Available protein structures:
Pfam   structures / ECOD  
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 initiates steroid production by mediating the delivery of cholesterol to the first enzyme in the 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.

Contents

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

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/aromatases. [4] [5]

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.

Mutations in STAR D9 (KIF16A) have been associated with a syndrome that includes severe ID, characteristic features, epilepsy, acquired microcephaly, and blindness. [6] The STAR D9 gene encodes a 4.7 kiloDalton amino acid protein which is a member of the kinesin superfamily. C-terminally truncated STAR D9 mutants are known from experimental work to induce spindle assembly defects. In the reported case, several mitotic defects including multipolar spindle formation, fragmentation of pericentriolar materials, and centrosome amplification were found.

Cholesterol/oxysterol binding StarD1/D3 subfamily

These proteins are primarily concerned with cholesterol transport

StAR (STARD1)
MLN64 (STARD3)

StarD4 subfamily

These proteins are involved in cholesterol and oxysterol transport

STARD4
STARD5
STARD6

Phospholipid/sphingolipid binding StarD2 subfamily

Phosphatidylcholine transfer protein (PCTP/STARD2)
STARD7
STARD10
Collagen type IV alpha-3-binding protein (COL4A3BP/Ceramide transfer protein (CERT)/STARD11)

SAM-RhoGAP-START subfamily

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

STARD8 (DLC-3)
DLC1 (STARD12)
STARD13 (DLC-2)

Acyl-CoA thioesterase subfamily

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

ACOT11 (STARD14)
ACOT12 (STARD15)

See also

Related Research Articles

<span class="mw-page-title-main">Peripheral membrane protein</span> Membrane proteins that adhere temporarily to membranes with which they are associated

Peripheral membrane proteins, or extrinsic membrane proteins, are membrane proteins that adhere only temporarily to the biological membrane with which they are associated. These proteins attach to integral membrane proteins, or penetrate the peripheral regions of the lipid bilayer. The regulatory protein subunits of many ion channels and transmembrane receptors, for example, may be defined as peripheral membrane proteins. In contrast to integral membrane proteins, peripheral membrane proteins tend to collect in the water-soluble component, or fraction, of all the proteins extracted during a protein purification procedure. Proteins with GPI anchors are an exception to this rule and can have purification properties similar to those of integral membrane proteins.

<span class="mw-page-title-main">Sterol regulatory element-binding protein</span> Protein family

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes SREBF1 and SREBF2. SREBPs belong to the basic-helix-loop-helix leucine zipper class of transcription factors. Unactivated SREBPs are attached to the nuclear envelope and endoplasmic reticulum membranes. In cells with low levels of sterols, SREBPs are cleaved to a water-soluble N-terminal domain that is translocated to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences, thus upregulating the synthesis of enzymes involved in sterol biosynthesis. Sterols in turn inhibit the cleavage of SREBPs and therefore synthesis of additional sterols is reduced through a negative feed back loop.

The steroidogenic acute regulatory protein, commonly referred to as StAR (STARD1), is a transport protein that regulates cholesterol transfer within the mitochondria, which is the rate-limiting step in the production of steroid hormones. It is primarily present in steroid-producing cells, including theca cells and luteal cells in the ovary, Leydig cells in the testis and cell types in the adrenal cortex.

<span class="mw-page-title-main">Liver X receptor</span> Nuclear receptor

The liver X receptor (LXR) is a member of the nuclear receptor family of transcription factors and is closely related to nuclear receptors such as the PPARs, FXR and RXR. Liver X receptors (LXRs) are important regulators of cholesterol, fatty acid, and glucose homeostasis. LXRs were earlier classified as orphan nuclear receptors, however, upon discovery of endogenous oxysterols as ligands they were subsequently deorphanized.

<span class="mw-page-title-main">CRAL-TRIO domain</span>

CRAL-TRIO domain is a protein structural domain that binds small lipophilic molecules. This domain is named after cellular retinaldehyde-binding protein (CRALBP) and TRIO guanine exchange factor.

<span class="mw-page-title-main">Sterol carrier protein</span>

Sterol carrier proteins is a family of proteins that transfer steroids and probably also phospholipids and gangliosides between cellular membranes.

<span class="mw-page-title-main">Sterol regulatory element-binding protein 1</span> Protein-coding gene in the species Homo sapiens

Sterol regulatory element-binding transcription factor 1 (SREBF1) also known as sterol regulatory element-binding protein 1 (SREBP-1) is a protein that in humans is encoded by the SREBF1 gene.

<span class="mw-page-title-main">ACOT8</span> Protein-coding gene in the species Homo sapiens

Acyl-coenzyme A thioesterase 8 is an enzyme that in humans is encoded by the ACOT8 gene.

<span class="mw-page-title-main">Oxysterol-binding protein</span>

The oxysterol-binding protein (OSBP)-related proteins (ORPs) are a family of lipid transfer proteins (LTPs). Concretely, they constitute a family of sterol and phosphoinositide binding and transfer proteins in eukaryotes that are conserved from yeast to humans. They are lipid-binding proteins implicated in many cellular processes related with oxysterol, including signaling, vesicular trafficking, lipid metabolism, and nonvesicular sterol transport.

<span class="mw-page-title-main">OSBP</span> Protein-coding gene in the species Homo sapiens

Oxysterol-binding protein 1 is a protein that in humans is encoded by the OSBP gene.

<span class="mw-page-title-main">STARD5</span> Protein-coding gene in the species Homo sapiens

StAR-related lipid transfer protein 5 is a protein that in humans is encoded by the STARD5 gene. The protein is a 213 amino acids long, consisting almost entirely of a StAR-related transfer (START) domain. It is also part of the StarD4 subfamily of START domain proteins, sharing 34% sequence identity with STARD4.

<span class="mw-page-title-main">ACOT11</span> Protein-coding gene in the species Homo sapiens

Acyl-coenzyme A thioesterase 11 also known as StAR-related lipid transfer protein 14 (STARD14) is an enzyme that in humans is encoded by the ACOT11 gene. This gene encodes a protein with acyl-CoA thioesterase activity towards medium (C12) and long-chain (C18) fatty acyl-CoA substrates which relies on its StAR-related lipid transfer domain. Expression of a similar murine protein in brown adipose tissue is induced by cold exposure and repressed by warmth. Expression of the mouse protein has been associated with obesity, with higher expression found in obesity-resistant mice compared with obesity-prone mice. Alternative splicing results in two transcript variants encoding different isoforms.

<span class="mw-page-title-main">STARD10</span> Protein-coding gene in the species Homo sapiens

StAR-related lipid transfer protein 10 (STARD10) or PCTP-like protein is a lipid transfer protein that in humans is encoded by the STARD10 gene. The protein derives its name from the fact that the molecule contains a START domain. As part of the StarD2 subfamily, StarD10 can transport the lipids phosphatidylcholine and phosphatidylethanolamine between membranes in solution. Casein kinase II phosphorylates the protein on its serine at position 184.

<span class="mw-page-title-main">Phosphatidylcholine transfer protein</span> Intracellular phospholipid binding protein

Phosphatidylcholine transfer protein (PCTP), also known as StAR-related lipid transfer domain protein 2 (STARD2), is a specific intracellular phospholipid binding protein that can transfer phosphatidylcholine between different membranes in the cytosol.

<span class="mw-page-title-main">STARD7</span> Protein-coding gene in the species Homo sapiens

StAR-related lipid transfer domain protein 7 (STARD7) or gestational trophoblastic tumor gene-1 (GTT1) is a lipid transporter that specifically binds and transports phosphatidylcholine between membranes.

<span class="mw-page-title-main">STARD4</span> Protein-coding gene in the species Homo sapiens

StAR-related lipid transfer protein 4 (STARD4) is a soluble protein involved in cholesterol transport. It can transfer up to 7 sterol molecules per minute between artificial membranes.

<span class="mw-page-title-main">ACOT13</span> Protein-coding gene in the species Homo sapiens

Acyl-CoA thioesterase 13 is a protein that in humans is encoded by the ACOT13 gene. This gene encodes a member of the thioesterase superfamily. In humans, the protein co-localizes with microtubules and is essential for sustained cell proliferation.

<span class="mw-page-title-main">ACOT1</span> Protein-coding gene in the species Homo sapiens

Acyl-CoA thioesterase 1 is a protein that in humans is encoded by the ACOT1 gene.

<span class="mw-page-title-main">Star related lipid transfer domain containing 3</span>

StAR related lipid transfer domain containing 3(STARD3) is a protein that in humans is encoded by the STARD3 gene. STARD3 also known as metastatic lymph node 64 protein (MLN64) is a late endosomal integral membrane protein involved in cholesterol transport. STARD3 creates membrane contact sites between the endoplasmic reticulum (ER) and late endosomes where it moves cholesterol.

VAD1 analog of StAR-related lipid transfer (VASt) is a steroidogenic acute regulatory protein‐related lipid transfer (StART)-like lipid-binding domain first identified in the vad1 protein in Arabidopsis thaliana. Proteins containing these domains are found in eukaryotes and usually contain another lipid-binding domain, typically the GRAM domain and sometimes the C2 domain in plants and the integral peroxisomal membrane peroxin Pex24p domain in oomycetes.

References

  1. 1 2 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.
  2. 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.
  3. 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 (6): R41. doi:10.1186/gb-2004-5-6-r41. PMC   463074 . PMID   15186492.
  4. 1 2 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.
  5. 1 2 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. S2CID   10806665.
  6. Okamoto N, Tsuchiya Y, Miya F, Tsunoda T, Yamashita K, Boroevich KA, Kato M, Saitoh S, Yamasaki M, Kanemura Y, Kosaki K, Kitagawa D (2017) A novel genetic syndrome with STARD9 mutation and abnormal spindle morphology. Am J Med Genet
This article incorporates text from the public domain Pfam and InterPro: IPR002913