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, res ...
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 mem ...
transport. STARD3 creates membrane contact sites between the 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 ca ...
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
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 mem ...
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
-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 class ...
.
The closest homolog to STARD3 is the steroidogenic acute regulatory protein (StAR/StarD1), which initiates the production of steroids by moving cholesterol inside the mitochondrion. 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 that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...
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
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-
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 class ...
(two phenylalanines in an acidic tract), and a C-terminal StAR-related transfer domain (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
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, res ...
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 angles ...
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
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...
, MLN64 is detectable in many but not all cells. Many
malignant tumors
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal bl ...
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>