Steroidogenic acute regulatory protein
Encyclopedia
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
.
needs to be transferred from the outer mitochondrial membrane to the inner membrane where cytochrome
P450scc enzyme
cleaves the cholesterol side chain, which is the first enzymatic step in all steroid synthesis. The aqueous phase between these two membranes cannot be crossed by the lipophilic
cholesterol, unless certain proteins assist in this process. A number of proteins have historically been proposed to facilitate this transfer including: sterol carrier protein
2 (SCP2), steroidogenic activator polypeptide (SAP), peripheral benzodiazepine receptor (PBR or translocator protein, TSPO), and StAR. It is now clear that this process is primarily mediated by the action of StAR.
The mechanism by which StAR causes cholesterol movement remains unclear as it appears to act from the outside of the mitochondria and its entry into the mitochondria ends its function. Various hypotheses have been advanced. Some involve StAR transferring cholesterol itself like a shuttle. While StAR may bind cholesterol itself, the exorbitant number of cholesterol molecules that the protein transfers would indicate that it would have to act as a cholesterol channel instead of a shuttle. Another notion is that it causes cholesterol to be kicked out of the outer membrane to the inner (cholesterol desorption). StAR may also promote the formation of contact sites between the outer and inner mitochondrial membranes to allow cholesterol influx. Another suggests that StAR acts in conjunction with PBR, causing the movement of Cl- out of the mitochondria to facilitate contact site formation. However, evidence for an interaction between StAR and PBR remains elusive.
at the serine
at position 195 increases its activity.
The domain of StAR important for promoting cholesterol transfer is the StAR-related transfer domain
(START domain). StAR is the prototypic member of the START domain family of proteins and is thus also known as STARD1 for "START domain-containing protein 1". It is hypothesized that the START domain forms a pocket in StAR that binds single cholesterol
molecules for delivery to P450scc.
The closest homolog
to StAR is MLN64
(STARD3). Together they comprise the StarD1/D3 subfamily of START domain-containing proteins.
(LH), ACTH and angiotensin II
.
At the cellular level, StAR is synthesized typically in response to activation of the cAMP
second messenger system
, although other systems can be involved even independently of cAMP
.
StAR has thus far been found in all tissues that can produce steroids, including the adrenal cortex, the gonad
s, the brain
and placenta
. One known exception is the human placenta.
Alcohol
suppresses StAR activity.
(lipoid CAH), in which patients produce little steroid and can die shortly after birth. Mutations that less severely affect the function of StAR result in nonclassic lipoid CAH or familial glucocorticoid deficiency type 3.
All known mutations disrupt StAR function by altering its START domain. In the case of StAR mutation, the phenotype does not present until birth since human placental steroidogenesis is independent of StAR.
At the cellular level, the lack of StAR results in a pathologic accumulation of lipid
within cells, especially noticeable in the adrenal cortex as seen in the mouse model. The testes are undescended and the resident steroidogenic Leydig cells are modestly affected. Early in life, the ovary
is spared as it does not express StAR until puberty. After puberty, lipid accumulations and hallmarks of ovarian failure are noted.
, these pathways are considered minor for endocrine production.
It is unclear what factors catalyze StAR-independent steroidogenesis. Candidates include oxysterols which can be freely converted to steroid and the ubiquitous MLN64
.
. This enzyme converts cholesterol to 27-hydroxycholesterol. In this way it may be important for the first step in one of the two pathways for the production of bile acids by the liver
(the alternative pathway).
Evidence also shows that the presence of StAR in a type of immune cell
, the macrophage
, where it can stimulate the production of 27-hydroxycholesterol. In this case, 27-hydroxycholesterol may by itself be helpful against the production of inflammatory
factors associated with cardiovascular disease
. It is important to note that no study has yet found a link between the loss of StAR and problems in bile acid production or increased risk for cardiovascular disease.
Transport protein
A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, or macromolecules, such as another protein across a biological membrane. Transport proteins are integral membrane proteins; that is they exist within and span the membrane across which they...
that regulates cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
transfer within the mitochondria, which is the rate-limiting step in the production of steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
hormones. It is primarily present in steroid-producing cells, including theca cells and luteal cells in the ovary
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...
, Leydig cells in the testis and cell types in the adrenal cortex
Adrenal cortex
Situated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis.-Layers:Notably, the reticularis in...
.
Function
CholesterolCholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
needs to be transferred from the outer mitochondrial membrane to the inner membrane where cytochrome
Cytochrome
Cytochromes are, in general, membrane-bound hemoproteins that contain heme groups and carry out electron transport.They are found either as monomeric proteins or as subunits of bigger enzymatic complexes that catalyze redox reactions....
P450scc enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
cleaves the cholesterol side chain, which is the first enzymatic step in all steroid synthesis. The aqueous phase between these two membranes cannot be crossed by the lipophilic
Lipophilic
Lipophilicity, , refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. These non-polar solvents are themselves lipophilic — the axiom that like dissolves like generally holds true...
cholesterol, unless certain proteins assist in this process. A number of proteins have historically been proposed to facilitate this transfer including: sterol carrier protein
Sterol carrier protein
Sterol carrier proteins is a family of proteins that transfer steroids and probably also phospholipids and gangliosides between cellular membranes....
2 (SCP2), steroidogenic activator polypeptide (SAP), peripheral benzodiazepine receptor (PBR or translocator protein, TSPO), and StAR. It is now clear that this process is primarily mediated by the action of StAR.
The mechanism by which StAR causes cholesterol movement remains unclear as it appears to act from the outside of the mitochondria and its entry into the mitochondria ends its function. Various hypotheses have been advanced. Some involve StAR transferring cholesterol itself like a shuttle. While StAR may bind cholesterol itself, the exorbitant number of cholesterol molecules that the protein transfers would indicate that it would have to act as a cholesterol channel instead of a shuttle. Another notion is that it causes cholesterol to be kicked out of the outer membrane to the inner (cholesterol desorption). StAR may also promote the formation of contact sites between the outer and inner mitochondrial membranes to allow cholesterol influx. Another suggests that StAR acts in conjunction with PBR, causing the movement of Cl- out of the mitochondria to facilitate contact site formation. However, evidence for an interaction between StAR and PBR remains elusive.
Structure
In humans, the gene for StAR is located on chromosome 8p11.2 and the protein has 285 amino acids. The signal sequence of StAR that targets it to the mitochondria is clipped off in two steps with import into the mitochondria. PhosphorylationPhosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
at the serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
at position 195 increases its activity.
The domain of StAR important for promoting cholesterol transfer is the StAR-related transfer domain
StAR-related transfer domain
START is a lipid-binding domain in StAR, HD-ZIP and signalling proteins. The archetypical domain is found in StAR , 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...
(START domain). StAR is the prototypic member of the START domain family of proteins and is thus also known as STARD1 for "START domain-containing protein 1". It is hypothesized that the START domain forms a pocket in StAR that binds single cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
molecules for delivery to P450scc.
The closest homolog
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
to StAR is MLN64
MLN64
StAR-related lipid transfer domain protein 3 also known as metastatic lymph node 64 protein is a late endosomal integral membrane protein involved in cholesterol transport.-Function:...
(STARD3). Together they comprise the StarD1/D3 subfamily of START domain-containing proteins.
Production
StAR is a mitochondrial protein that is rapidly synthesized in response to stimulation of the cell to produce steroid. Hormones that stimulate its production depend on the cell type and include luteinizing hormoneLuteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
(LH), ACTH and angiotensin II
Angiotensin
Angiotensin, a peptide hormone, causes blood vessels to constrict, and drives blood pressure up. It is part of the renin-angiotensin system, which is a major target for drugs that lower blood pressure. Angiotensin also stimulates the release of aldosterone, another hormone, from the adrenal cortex...
.
At the cellular level, StAR is synthesized typically in response to activation of the cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
second messenger system
Second messenger system
Second messengers are molecules that relay signals from receptors on the cell surface to target molecules inside the cell, in the cytoplasm or nucleus. They relay the signals of hormones like epinephrine , growth factors, and others, and cause some kind of change in the activity of the cell...
, although other systems can be involved even independently of cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
.
StAR has thus far been found in all tissues that can produce steroids, including the adrenal cortex, the gonad
Gonad
The gonad is the organ that makes gametes. The gonads in males are the testes and the gonads in females are the ovaries. The product, gametes, are haploid germ cells. For example, spermatozoon and egg cells are gametes...
s, the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
and placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
. One known exception is the human placenta.
Alcohol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
suppresses StAR activity.
Pathology
Mutations in the gene for StAR cause lipoid congenital adrenal hyperplasiaLipoid congenital adrenal hyperplasia
Lipoid congenital adrenal hyperplasia is an endocrine disorder that is an uncommon and potentially lethal form of congenital adrenal hyperplasia...
(lipoid CAH), in which patients produce little steroid and can die shortly after birth. Mutations that less severely affect the function of StAR result in nonclassic lipoid CAH or familial glucocorticoid deficiency type 3.
All known mutations disrupt StAR function by altering its START domain. In the case of StAR mutation, the phenotype does not present until birth since human placental steroidogenesis is independent of StAR.
At the cellular level, the lack of StAR results in a pathologic accumulation of lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
within cells, especially noticeable in the adrenal cortex as seen in the mouse model. The testes are undescended and the resident steroidogenic Leydig cells are modestly affected. Early in life, the ovary
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...
is spared as it does not express StAR until puberty. After puberty, lipid accumulations and hallmarks of ovarian failure are noted.
StAR-Independent Steroidogenesis
While loss of functional StAR in the human and the mouse catastrophically reduces steroid production, it does not eliminate all of it, indicating the existence of StAR-independent pathways for steroid generation. Aside from the human placentaPlacenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
, these pathways are considered minor for endocrine production.
It is unclear what factors catalyze StAR-independent steroidogenesis. Candidates include oxysterols which can be freely converted to steroid and the ubiquitous MLN64
MLN64
StAR-related lipid transfer domain protein 3 also known as metastatic lymph node 64 protein is a late endosomal integral membrane protein involved in cholesterol transport.-Function:...
.
New Roles for StAR
Recent findings suggest that StAR may also traffic cholesterol to a second mitochondrial enzyme, sterol 27-hydroxylaseCYP27A1
CYP27A1 is a gene encoding a cytochrome P450 oxidase, and is commonly known as sterol 27-hydroxylase. This enzyme is located in many different tissues where it is found within the mitochondria. It is most prominently involved in the biosynthesis of bile acids.-Function:CYP27A1 participates in the...
. This enzyme converts cholesterol to 27-hydroxycholesterol. In this way it may be important for the first step in one of the two pathways for the production of bile acids by the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
(the alternative pathway).
Evidence also shows that the presence of StAR in a type of immune cell
White blood cell
White blood cells, or leukocytes , are cells of the immune system involved in defending the body against both infectious disease and foreign materials. Five different and diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow known as a...
, the macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
, where it can stimulate the production of 27-hydroxycholesterol. In this case, 27-hydroxycholesterol may by itself be helpful against the production of inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
factors associated with cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
. It is important to note that no study has yet found a link between the loss of StAR and problems in bile acid production or increased risk for cardiovascular disease.