StAR related lipid transfer domain containing 3 (STARD3) is a protein that in humans is encoded by the STARD3 gene.[5] STARD3 also known as metastatic lymph node 64 protein (MLN64) is a late endosomal integral membrane protein involved in cholesterol transport.[6] STARD3 creates membrane contact sites between the endoplasmic reticulum (ER) and late endosomes where it moves cholesterol.[7][8]
| STARD3 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | STARD3, CAB1, MLN64, es64, StAR related lipid transfer domain containing 3 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 607048; MGI: 1929618; HomoloGene: 38227; GeneCards: STARD3; OMA:STARD3 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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.[provided by RefSeq, Oct 2009].
STARD3 is involved in cholesterol transport from the ER to late endosomes where the protein is anchored.[9][10] 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 together.[11] For STARD3, this interaction is regulated by phosphorylation of a serine in its FFAT motif.[12]
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 which lacks StAR yet produces steroids.[13] This functional role is supported by evidence that MLN64 expression can stimulate steroid production in a model cell system.[13]
One study indicates that this protein also specifically binds lutein in the retina.[14]
Structure
STARD3 is a multi-domain protein composed of a N-terminal MENTAL (MLN64 N-terminal) domain, a central phospho-FFAT motif (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).[15] 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.[16]
The phospho-FFAT motif is a short protein sequence motif which binds to the ER proteins VAP-A, VAP-B and MOSPD2 proteins after phosphorylation.[12]
The START domain of STARD3 is homologous to the StAR protein. X-ray crystallography of the C-terminus indicates that this domain forms a pocket that can bind cholesterol.[17] 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, MLN64 is detectable in many but not all cells.[18] Many malignant tumors highly express STARD3 as a result of its gene being part of a Her2/erbB2-containing gene locus that is amplified.
Pathology
Loss of STARD3 has little effect in mice.[19] At the cellular level, changes in STARD3 can disrupt trafficking of endosomes and cause accumulation of cholesterol in late endosomes.[20]
References
Further reading
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