Biology:Star related lipid transfer domain containing 3

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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 (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.[9]

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]

References

  1. ↑ "Entrez Gene: StAR related lipid transfer domain containing 3". https://www.ncbi.nlm.nih.gov/gene/10948. 
  2. ↑ "MLN64 and MENTHO, two mediators of endosomal cholesterol transport". Biochemical Society Transactions 34 (Pt 3): 343–5. June 2006. doi:10.1042/BST0340343. PMID 16709157. 
  3. ↑ "STARD3 mediates endoplasmic reticulum-to-endosome cholesterol transport at membrane contact sites". The EMBO Journal 36 (10): 1412–1433. May 2017. doi:10.15252/embj.201695917. PMID 28377464. 
  4. ↑ "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. doi:10.1242/jcs.139295. PMID 24105263. 
  5. ↑ "STARD3 mediates endoplasmic reticulum-to-endosome cholesterol transport at membrane contact sites". The EMBO Journal 36 (10): 1412–1433. May 2017. doi:10.15252/embj.201695917. PMID 28377464. 
  6. ↑ "The steroidogenic acute regulatory protein homolog MLN64, a late endosomal cholesterol-binding protein". The Journal of Biological Chemistry 276 (6): 4261–9. February 2001. doi:10.1074/jbc.M006279200. PMID 11053434. 
  7. ↑ "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. doi:10.1242/jcs.139295. PMID 24105263. https://hal.archives-ouvertes.fr/hal-03409563/file/Alpy_ER-LE%20MCS_J%20Cell%20Sci_2013_SmallSize.pdf. 
  8. ↑ 8.0 8.1 Di Mattia, Thomas; Martinet, Arthur; Ikhlef, Souade; McEwen, Alastair G; Nominé, Yves; Wendling, Corinne; Poussin-Courmontagne, Pierre; Voilquin, Laetitia et al. (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. PMID 33124732. 
  9. ↑ 9.0 9.1 "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. doi:10.1073/pnas.94.16.8462. PMID 9237999. Bibcode: 1997PNAS...94.8462W. 
  10. ↑ "Identification of StARD3 as a lutein-binding protein in the macula of the primate retina". Biochemistry 50 (13): 2541–9. April 2011. doi:10.1021/bi101906y. PMID 21322544. 
  11. ↑ "MENTHO, a MLN64 homologue devoid of the START domain". The Journal of Biological Chemistry 277 (52): 50780–7. December 2002. doi:10.1074/jbc.M208290200. PMID 12393907. 
  12. ↑ "Functional characterization of the MENTAL domain". The Journal of Biological Chemistry 280 (18): 17945–52. May 2005. doi:10.1074/jbc.M500723200. PMID 15718238. 
  13. ↑ "Structure and lipid transport mechanism of a StAR-related domain". Nature Structural Biology 7 (5): 408–14. May 2000. doi:10.1038/75192. PMID 10802740. 
  14. ↑ "Characterization of the putative cholesterol transport protein metastatic lymph node 64 in the brain". Neuroscience 139 (3): 1031–8. 2006. doi:10.1016/j.neuroscience.2006.01.063. PMID 16549269. 
  15. ↑ "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. doi:10.1074/jbc.M400717200. PMID 14963026. 
  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

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.




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