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]
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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]
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.
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.
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. PMID 16709157. Alpy F, Rousseau A, Schwab Y, Legueux F, Stoll I, Wendling C, Spiegelhalter C, Kessler P, Mathelin C, Rio MC, Levine TP, Tomasetto C (December 2013). "STARD3 or STARD3NL and VAP form a novel molecular tether between late endosomes and the ER". Journal of Cell Science. 126 (Pt 23): 5500–12. doi:10.1242/jcs.139295. PMID 24105263. Alpy F, Stoeckel ME, Dierich A, Escola JM, Wendling C, Chenard MP, Vanier MT, Gruenberg J, Tomasetto C, Rio MC (February 2001). "The steroidogenic acute regulatory protein homolog MLN64, a late endosomal cholesterol-binding protein". The Journal of Biological Chemistry. 276 (6): 4261–9. doi:10.1074/jbc.M006279200. PMID 11053434. Alpy F, Rousseau A, Schwab Y, Legueux F, Stoll I, Wendling C, Spiegelhalter C, Kessler P, Mathelin C, Rio MC, Levine TP, Tomasetto C (December 1, 2013). "STARD3 or STARD3NL and VAP form a novel molecular tether between late endosomes and the ER" (PDF). J Cell Sci. 126 (23): 5500–5512. doi:10.1242/jcs.139295. PMID 24105263. S2CID 7245863. Di Mattia, Thomas; Martinet, Arthur; Ikhlef, Souade; McEwen, Alastair G; Nominé, Yves; Wendling, Corinne; Poussin-Courmontagne, Pierre; Voilquin, Laetitia; Eberling, Pascal; Ruffenach, Frank; Cavarelli, Jean; Slee, John; Levine, Timothy P; Drin, Guillaume; Tomasetto, Catherine; Alpy, Fabien (December 1, 2020). "FFAT motif phosphorylation controls formation and lipid transfer function of inter-organelle contacts". The EMBO Journal. 39 (23): e104369. doi:10.15252/embj.2019104369. ISSN 0261-4189. PMC 7705450. PMID 33124732. 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
- Zhang M, Liu P, Dwyer NK, Christenson LK, Fujimoto T, Martinez F, Comly M, Hanover JA, Blanchette-Mackie EJ, Strauss JF (September 2002). "MLN64 mediates mobilization of lysosomal cholesterol to steroidogenic mitochondria". The Journal of Biological Chemistry. 277 (36): 33300–10. doi:10.1074/jbc.M200003200. PMID 12070139.
- 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. PMID 12398991. S2CID 25185703.
- Tuckey RC, Bose HS, Czerwionka I, Miller WL (April 2004). "Molten globule structure and steroidogenic activity of N-218 MLN64 in human placental mitochondria". Endocrinology. 145 (4): 1700–7. doi:10.1210/en.2003-1034. PMID 14715710.
- 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. PMID 15010812.
- Alpy F, Latchumanan VK, Kedinger V, Janoshazi A, Thiele C, Wendling C, Rio MC, Tomasetto C (May 2005). "Functional characterization of the MENTAL domain". The Journal of Biological Chemistry. 280 (18): 17945–52. doi:10.1074/jbc.M500723200. PMID 15718238.
- Hölttä-Vuori M, Alpy F, Tanhuanpää K, Jokitalo E, Mutka AL, Ikonen E (August 2005). "MLN64 is involved in actin-mediated dynamics of late endocytic organelles". Molecular Biology of the Cell. 16 (8): 3873–86. doi:10.1091/mbc.e04-12-1105. PMC 1182323. PMID 15930133.
- 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. PMID 16709157.
- Murcia M, Faráldo-Gómez JD, Maxfield FR, Roux B (December 2006). "Modeling the structure of the StART domains of MLN64 and StAR proteins in complex with cholesterol". Journal of Lipid Research. 47 (12): 2614–30. doi:10.1194/jlr.M600232-JLR200. PMID 16990645.
- Benusiglio PR, Pharoah PD, Smith PL, Lesueur F, Conroy D, Luben RN, Dew G, Jordan C, Dunning A, Easton DF, Ponder BA (December 2006). "HapMap-based study of the 17q21 ERBB2 amplicon in susceptibility to breast cancer". British Journal of Cancer. 95 (12): 1689–95. doi:10.1038/sj.bjc.6603473. PMC 2360759. PMID 17117180.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
