StAR related lipid transfer domain containing 3 (STARD3) is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...

that in humans is encoded by the STARD3

gene In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...

. STARD3 also known as metastatic lymph node 64 protein (MLN64) is a late endosomal

integral membrane protein An integral, or intrinsic, membrane protein (IMP) is a type of membrane protein that is permanently attached to the biological membrane. All ''transmembrane proteins'' are IMPs, but not all IMPs are transmembrane proteins. IMPs comprise a sign ...

involved in

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell membr ...

transport. STARD3 creates membrane contact sites between the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

(ER) and late

endosomes Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane ...

where it moves cholesterol.

Function

This gene encodes a member of a subfamily of lipid trafficking proteins that are characterized by a C-terminal steroidogenic acute regulatory domain and an N-terminal metastatic lymph node 64 domain. The encoded protein localizes to the membranes of late endosomes and may be involved in exporting cholesterol. Alternative splicing results in multiple transcript variants. rovided by RefSeq, Oct 2009 STARD3 is involved in

transport from the ER to late endosomes where the protein is anchored. It forms a complex with fellow late endosomal protein STARD3 N-terminal-like protein ( STARD3NL) also known as MLN64 N-terminal homologue ( MENTHO) and ER VAMP-associated proteins (VAP proteins) A and B ( VAP-A, VAP-B) to tether the two

organelles In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' th ...

together. For STARD3, this interaction is regulated by phosphorylation of a serine in its

FFAT motif A FFAT motif (FFAT being an acronym for two phenylalanines (FF) in an acidic tract) is a protein sequence motif of six defined amino acids plus neighbouring residues that binds to proteins in the VAP protein family. Initial definition The classic ...

. The closest homolog to STARD3 is the

steroidogenic acute regulatory protein 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 ...

(StAR/StarD1), which initiates the production of steroids by moving cholesterol inside the

mitochondrion A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is use ...

. Thus, MLN64 is also proposed to move cholesterol inside the mitochondria under certain conditions to initiate StAR-independent steroidogenesis, such as in the human

placenta The placenta is a temporary embryonic and later fetal organ (anatomy), organ that begins embryonic development, developing from the blastocyst shortly after implantation (embryology), implantation. It plays critical roles in facilitating nutrien ...

which lacks StAR yet produces steroids. This functional role is supported by evidence that MLN64 expression can stimulate steroid production in a model cell system. One study indicates that this protein also specifically binds

lutein Lutein (;"Lutein"

retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...

Structure

STARD3 is a multi-domain protein composed of a N-terminal MENTAL (MLN64 N-terminal) domain, a central phospho-

(two phenylalanines in an acidic tract), and a C-terminal

StAR-related transfer domain 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-pro ...

(START) lipid transport domain. The MENTAL domain of STARD3 is similar to the protein STARD3 N-terminal like protein ( STARD3NL) also known as MLN64 N-terminal homologue ( MENTHO). This domain is composed of 4 transmembrane helices which anchor the protein in the limiting membrane of late endosomes. This domain binds cholesterol and associates with the same domain in STARD3NL. The phospho-FFAT motif is a short

sequence motif In biology, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and usually assumed to be related to biological function of the macromolecule. For example, an ''N''-glycosylation site motif can be defined as '' ...

which binds to the ER proteins VAP-A, VAP-B and MOSPD2 proteins after

phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...

. The START domain of STARD3 is

homologous Homology may refer to: Sciences Biology *Homology (biology), any characteristic of biological organisms that is derived from a common ancestor *Sequence homology, biological homology between DNA, RNA, or protein sequences * Homologous chrom ...

to the

StAR A star is an astronomical object comprising a luminous spheroid of plasma held together by its gravity. The nearest star to Earth is the Sun. Many other stars are visible to the naked eye at night, but their immense distances from Earth make ...

protein.

X-ray crystallography X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angle ...

of the C-terminus indicates that this domain forms a pocket that can bind cholesterol. This places STARD3 within the StarD1/D3 subfamily of START domain-containing proteins.

Tissue distribution

STARD3 is expressed in all tissues in the body at various levels. In the

brain The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head ( cephalization), usually near organs for special ...

, MLN64 is detectable in many but not all cells. Many malignant tumors highly express STARD3 as a result of its gene being part of a Her2/

erbB2 Receptor tyrosine-protein kinase erbB-2 is a protein that in humans is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently refer ...

-containing gene

locus Locus (plural loci) is Latin for "place". It may refer to: Entertainment * Locus (comics), a Marvel Comics mutant villainess, a member of the Mutant Liberation Front * ''Locus'' (magazine), science fiction and fantasy magazine ** ''Locus Award ...

that is amplified.

Pathology

Loss of STARD3 has little effect in mice. At the cellular level, changes in STARD3 can disrupt trafficking of endosomes and cause accumulation of cholesterol in late endosomes.Zhang M, Liu P, Dwyer NK, Christenson LK, Fujimoto T, Martinez F, Comly M, Hanover JA, Blanchette‐Mackie EJ, Strauss JF (2002) MLN64 mediates mobilization of lysosomal cholesterol to steroidogenic mitochondria. J Biol Chem 277: 33300–33310 [PubMed
doi: 10.1074/jbc.M200003200
/ref>

Function

Structure

Tissue distribution

Pathology

References

Further reading