Star related lipid transfer domain containing 3 explained

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 (ER) 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 ER to late endosomes where the protein is anchored.[5] [6] 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.[7] For STARD3, this interaction is regulated by phosphorylation of a serine in its FFAT motif.[8]

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.[9] 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 lutein in the retina.[10]

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).[11] 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.[12]

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.[8]

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.[13] 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.[14] 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.[15] At the cellular level, changes in STARD3 can disrupt trafficking of endosomes and cause accumulation of cholesterol in late endosomes.[16]

Further reading

Notes and References

  1. Web site: Entrez Gene: StAR related lipid transfer domain containing 3. 2018-08-07.
  2. Alpy F, Tomasetto C . MLN64 and MENTHO, two mediators of endosomal cholesterol transport . Biochemical Society Transactions . 34 . Pt 3 . 343–5 . June 2006 . 16709157 . 10.1042/BST0340343 .
  3. Wilhelm LP, Wendling C, Védie B, Kobayashi T, Chenard MP, Tomasetto C, Drin G, Alpy F . STARD3 mediates endoplasmic reticulum-to-endosome cholesterol transport at membrane contact sites . The EMBO Journal . 36 . 10 . 1412–1433 . May 2017 . 28377464 . 5430228 . 10.15252/embj.201695917 .
  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 . 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 . December 2013 . 24105263 . 10.1242/jcs.139295 . free .
  5. Wilhelm LP, Wendling C, Védie B, Kobayashi T, Chenard MP, Tomasetto C, Drin G, Alpy F . STARD3 mediates endoplasmic reticulum-to-endosome cholesterol transport at membrane contact sites . The EMBO Journal . 36 . 10 . 1412–1433 . May 2017 . 28377464 . 5430228 . 10.15252/embj.201695917 .
  6. Alpy F, Stoeckel ME, Dierich A, Escola JM, Wendling C, Chenard MP, Vanier MT, Gruenberg J, Tomasetto C, Rio MC . The steroidogenic acute regulatory protein homolog MLN64, a late endosomal cholesterol-binding protein . The Journal of Biological Chemistry . 276 . 6 . 4261–9 . February 2001 . 11053434 . 10.1074/jbc.M006279200 . free .
  7. Alpy F, Rousseau A, Schwab Y, Legueux F, Stoll I, Wendling C, Spiegelhalter C, Kessler P, Mathelin C, Rio MC, Levine TP, Tomasetto C . STARD3 or STARD3NL and VAP form a novel molecular tether between late endosomes and the ER . J Cell Sci . 126 . 23 . 5500–5512 . December 1, 2013 . 24105263 . 10.1242/jcs.139295 . 7245863 .
  8. 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. 10.15252/embj.2019104369. 0261-4189. 7705450. 33124732.
  9. Watari H, Arakane F, Moog-Lutz C, Kallen CB, Tomasetto C, Gerton GL, Rio MC, Baker ME, Strauss JF . 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 . August 1997 . 9237999 . 22957 . 10.1073/pnas.94.16.8462 . 1997PNAS...94.8462W . free .
  10. Li B, Vachali P, Frederick JM, Bernstein PS . Identification of StARD3 as a lutein-binding protein in the macula of the primate retina . Biochemistry . 50 . 13 . 2541–9 . April 2011 . 21322544 . 3070171 . 10.1021/bi101906y .
  11. Alpy F, Wendling C, Rio MC, Tomasetto C . MENTHO, a MLN64 homologue devoid of the START domain . The Journal of Biological Chemistry . 277 . 52 . 50780–7 . December 2002 . 12393907 . 10.1074/jbc.M208290200 . free .
  12. Alpy F, Latchumanan VK, Kedinger V, Janoshazi A, Thiele C, Wendling C, Rio MC, Tomasetto C . Functional characterization of the MENTAL domain . The Journal of Biological Chemistry . 280 . 18 . 17945–52 . May 2005 . 15718238 . 10.1074/jbc.M500723200 . free .
  13. Tsujishita Y, Hurley JH . Structure and lipid transport mechanism of a StAR-related domain . Nature Structural Biology . 7 . 5 . 408–14 . May 2000 . 10802740 . 10.1038/75192 . 10806665 .
  14. King SR, Smith AG, Alpy F, Tomasetto C, Ginsberg SD, Lamb DJ . Characterization of the putative cholesterol transport protein metastatic lymph node 64 in the brain . Neuroscience . 139 . 3 . 1031–8 . 2006 . 16549269 . 10.1016/j.neuroscience.2006.01.063 . 33113555 .
  15. Kishida T, Kostetskii I, Zhang Z, Martinez F, Liu P, Walkley SU, Dwyer NK, Blanchette-Mackie EJ, Radice GL, Strauss JF . Targeted mutation of the MLN64 START domain causes only modest alterations in cellular sterol metabolism . The Journal of Biological Chemistry . 279 . 18 . 19276–85 . April 2004 . 14963026 . 10.1074/jbc.M400717200 . free .
  16. 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

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