STARD3

StAR-related lipid transfer (START) domain containing 3
Identifiers
Symbol STARD3
Entrez 10948
HUGO 17579
OMIM 607048
RefSeq NM_006804
UniProt Q14849
Other data
Locus Chr. 17 q11-q12

StAR-related lipid transfer domain protein 3 (STARD3) also known as metastatic lymph node 64 protein (MLN64) is a late endosomal integral membrane protein involved in cholesterol transport.[1]

Function

MLN64 is hypothesized to regulate cholesterol transport between the late endosome where it is tethered and cytoplasmic membranes. Some data further suggest that endogenous MLN64 can cause cholesterol transport to the mitochondria.[2]

The closest homolog to MLN64 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.[3] This functional role is supported by evidence that MLN64 expression can stimulate steroid production in a model cell system.[3]

A recent study indicates that this protein also specifically binds lutein in the retina.[4]

Structure

Its C-terminus contains a StAR-related transfer domain (START) that is homologous to the StAR. X-ray crystallography of the C-terminus indicates that this domain forms a pocket that can bind cholesterol.[5] This places MLN64 within the StarD1/D3 subfamily of START domain-containing proteins.

The N-terminus consists of a MENTAL (MLN64 N-terminal) domain similar to the protein MLN64 N-terminal homologue (MENTHO) with unclear function. This domain is buried in the late endosomal membrane and may associate with the same domain in MENTHO.

Tissue distribution

MLN64 is expressed in all tissues in the body at various levels. In the brain, MLN64 is detectable in many but not all cells.[6] Many malignant tumors highly express MLN64 as a result of its gene being part of a Her2/erbB2-containing gene locus that is duplicated.

Pathology

Loss of MLN64 has little effect in mice.[7] At the cellular level, changes in MLN64 can disrupt trafficking of endosomes and cause accumulation of cholesterol in late endosomes.[8]

  1. ↑ Alpy F, Tomasetto C (June 2006). "MLN64 and MENTHO, two mediators of endosomal cholesterol transport". Biochem. Soc. Trans. 34 (Pt 3): 343–5. PMID 16709157. doi:10.1042/BST0340343.
  2. ↑ Charman M, Kennedy BE, Osborne N, Karten B (October 2009). "MLN64 mediates egress of cholesterol from endosomes to mitochondria in the absence of functional Niemann-Pick Type C1 protein". J. Lipid Res. 51 (5): 1023–34. PMID 19965586. doi:10.1194/jlr.M002345.
  3. 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". Proc. Natl. Acad. Sci. U.S.A. 94 (16): 8462–7. PMC 22957 Freely accessible. PMID 9237999. doi:10.1073/pnas.94.16.8462.
  4. ↑ 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. PMC 3070171 Freely accessible. PMID 21322544. doi:10.1021/bi101906y.
  5. ↑ Tsujishita Y, Hurley JH (May 2000). "Structure and lipid transport mechanism of a StAR-related domain". Nat. Struct. Biol. 7 (5): 408–14. PMID 10802740. doi:10.1038/75192.
  6. ↑ 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. PMID 16549269. doi:10.1016/j.neuroscience.2006.01.063.
  7. ↑ 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". J. Biol. Chem. 279 (18): 19276–85. PMID 14963026. doi:10.1074/jbc.M400717200.
  8. ↑ 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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