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 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]
^Alpy F, Tomasetto C (June 2006). "MLN64 and MENTHO, two mediators of endosomal cholesterol transport". Biochemical Society Transactions. 34 (Pt 3): 343–5. doi:10.1042/BST0340343. PMID16709157.
^Tsujishita Y, Hurley JH (May 2000). "Structure and lipid transport mechanism of a StAR-related domain". Nature Structural Biology. 7 (5): 408–14. doi:10.1038/75192. PMID10802740. S2CID10806665.
^King SR, Smith AG, Alpy F, Tomasetto C, Ginsberg SD, Lamb DJ (2006). "Characterization of the putative cholesterol transport protein metastatic lymph node 64 in the brain". Neuroscience. 139 (3): 1031–8. doi:10.1016/j.neuroscience.2006.01.063. PMID16549269. S2CID33113555.
Strauss JF, Liu P, Christenson LK, Watari H (November 2002). "Sterols and intracellular vesicular trafficking: lessons from the study of NPC1". Steroids. 67 (12): 947–51. doi:10.1016/s0039-128x(02)00042-9. PMID12398991. S2CID25185703.
Katoh M, Katoh M (April 2004). "Evolutionary recombination hotspot around GSDML-GSDM locus is closely linked to the oncogenomic recombination hotspot around the PPP1R1B-ERBB2-GRB7 amplicon". International Journal of Oncology. 24 (4): 757–63. doi:10.3892/ijo.24.4.757. PMID15010812.
Alpy F, Tomasetto C (June 2006). "MLN64 and MENTHO, two mediators of endosomal cholesterol transport". Biochemical Society Transactions. 34 (Pt 3): 343–5. doi:10.1042/BST0340343. PMID16709157.
