STARD3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSTARD3, CAB1, MLN64, es64, StAR related lipid transfer domain containing 3
External IDsOMIM: 607048 MGI: 1929618 HomoloGene: 38227 GeneCards: STARD3
Orthologs
SpeciesHumanMouse
Entrez

10948

59045

Ensembl

ENSG00000131748

ENSMUSG00000018167

UniProt

Q14849

Q61542

RefSeq (mRNA)

NM_001165937
NM_001165938
NM_006804

NM_021547

RefSeq (protein)

NP_001159409
NP_001159410
NP_006795

NP_067522

Location (UCSC)Chr 17: 39.64 – 39.66 MbChr 11: 98.25 – 98.27 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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]

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.[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 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.

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]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000131748 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000018167 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Entrez Gene: StAR related lipid transfer domain containing 3". Retrieved 2018-08-07.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. 1 2 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.
  13. 1 2 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. Bibcode:1997PNAS...94.8462W. doi:10.1073/pnas.94.16.8462. PMC 22957. PMID 9237999.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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. S2CID 10806665.
  18. ↑ 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. S2CID 33113555.
  19. ↑ 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.
  20. ↑ 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

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