Star related lipid transfer domain containing 3

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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StAR related lipid transfer domain containing 3 (STARD3) is a protein that in humans is encoded by the STARD3 gene.[1] STARD3 also known as metastatic lymph node 64 protein (MLN64) is a late endosomal integral membrane protein involved in cholesterol transport.[2] STARD3 creates membrane contact sites between the endoplasmic reticulum and late endosomes where it moves cholesterol.[3][4]

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 endoplasmic reticulum to late endosomes where the protein is anchored. [5][6]

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.[7] This functional role is supported by evidence that MLN64 expression can stimulate steroid production in a model cell system.[7]

A recent study indicates that this protein also specifically binds lutein in the retina.[8]

Structure

STARD3 is a multi-domain protein composed of a N-terminal MENTAL (MLN64 N-terminal) domain, a central 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).[9] 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.[10]

The FFAT motif is a short protein sequence motif which binds to the ER proteins VAP-A, VAP-B and MOSPD2 proteins.

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.[11] 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.[12] 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.[13] At the cellular level, changes in STARD3 can disrupt trafficking of endosomes and cause accumulation of cholesterol in late endosomes.[14]

References

  1. ↑ "Entrez Gene: StAR related lipid transfer domain containing 3". Retrieved 2018-08-07.
  2. ↑ 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.
  3. ↑ Wilhelm LP, Wendling C, Védie B, Kobayashi T, Chenard MP, Tomasetto C, Drin G, Alpy F (May 2017). "STARD3 mediates endoplasmic reticulum-to-endosome cholesterol transport at membrane contact sites". The EMBO Journal. 36 (10): 1412–1433. doi:10.15252/embj.201695917. PMC 5430228. PMID 28377464.
  4. ↑ 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.
  5. ↑ Wilhelm LP, Wendling C, Védie B, Kobayashi T, Chenard MP, Tomasetto C, Drin G, Alpy F (May 2017). "STARD3 mediates endoplasmic reticulum-to-endosome cholesterol transport at membrane contact sites". The EMBO Journal. 36 (10): 1412–1433. doi:10.15252/embj.201695917. PMC 5430228. PMID 28377464.
  6. ↑ 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.
  7. ↑ 7.0 7.1 Watari H, Arakane F, Moog-Lutz C, Kallen CB, Tomasetto C, Gerton GL, Rio MC, Baker ME, Strauss JF (August 1997). "MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis". Proceedings of the National Academy of Sciences of the United States of America. 94 (16): 8462–7. doi:10.1073/pnas.94.16.8462. PMC 22957. PMID 9237999.
  8. ↑ Li B, Vachali P, Frederick JM, Bernstein PS (April 2011). "Identification of StARD3 as a lutein-binding protein in the macula of the primate retina". Biochemistry. 50 (13): 2541–9. doi:10.1021/bi101906y. PMC 3070171. PMID 21322544.
  9. ↑ Alpy F, Wendling C, Rio MC, Tomasetto C (December 2002). "MENTHO, a MLN64 homologue devoid of the START domain". The Journal of Biological Chemistry. 277 (52): 50780–7. doi:10.1074/jbc.M208290200. PMID 12393907.
  10. ↑ 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.
  11. ↑ 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. PMID 10802740.
  12. ↑ 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. PMID 16549269.
  13. ↑ Kishida T, Kostetskii I, Zhang Z, Martinez F, Liu P, Walkley SU, Dwyer NK, Blanchette-Mackie EJ, Radice GL, Strauss JF (April 2004). "Targeted mutation of the MLN64 START domain causes only modest alterations in cellular sterol metabolism". The Journal of Biological Chemistry. 279 (18): 19276–85. doi:10.1074/jbc.M400717200. PMID 14963026.
  14. ↑ 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

Further reading

  • 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. PMID 12398991.
  • 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. 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.

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