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9.B.64 The Putative Cholesterol Transporter (Start1) Family

MLN64 (metastatic lymph node 64) and MENTHO (MLN64 N-terminal homologue) are two late-endosomal proteins that share a conserved region of four TMSs with three short intervening loops called the MENTAL domain (MLN64 N-terminal domain) (Alpy and Tomasetto 2006). This domain mediates MLN64 and MENTHO homo- and hetero-interactions, targets both proteins to late endosomes and binds cholesterol in vivo. In addition to the MENTAL domain, MLN64 contains a cholesterol-specific START domain [StAR (steroidogenic acute regulatory protein)-related lipid transfer domain]. The START domain is a protein module of approx. 210 residues that binds lipids, including sterols, and is present in 15 distinct proteins in mammals. They may function in cholesterol transport. The MENTAL domain might serve to maintain cholesterol at the membrane of late endosomes prior to its shuttle to cytoplasmic acceptor(s) through the START domain (Alpy and Tomasetto 2006).

The human metastatic lymph node 64 (MLN64) protein is a 4 TMS protein, where residues 52-170 in this 445 aa protein are transmembrane. The Drosophila melanogaster Start1 protein is a homologous 4 TMS protein where residues 62-183 in this 583 aa protein are transmembrane. Roth et al. (2004) proposed that Start1 is a cholesterol transporter.MLN64 transport to the late endosome is regulated by binding to the 14-3-3 protein (TC# 8.A.98.1.1)via a non-canonical binding site (Liapis et al. 2012). Steroid hormone biosynthesis in mitochondria has been reviewed (Miller 2013).

The two proteins, Start1 and MLN64, are homologous to the vertebrate cholesterol-binding steroid acute regulatory protein (STAR)-related lipid transfer domain (START). MLN64 is somehow involved in cholesterol trafficking and/or steroid synthesis. Roth et al. (2004) suggested that Start1 plays a role in the regulation of ecdysteroid synthesis, and expression of Start1 depends on ecdysone. These authors suggested that Start1 is a cholesterol transporter since ecdysteroid is synthesized from cholesterol. Another group, Kennedy et al. 2014  showed that MLN64, mediates endosomal cholesterol transport to mitochondria.

START domains are ~210 aa lipid binding domains implicated in intracellular lipid transport, lipid metabolism and cell signaling (Soccio and Breslow, 2003). The human and mouse genomes have 15 genes encoding START domains. The x-ray structures of three such proteins have been solved (see Soccio and Breslow, 2003 for a review).

References associated with 9.B.64 family:

Alpy, F. and C. Tomasetto. (2006). MLN64 and MENTHO, two mediators of endosomal cholesterol transport. Biochem Soc Trans 34: 343-345. 16709157
Arunkumar, R., A. Gorusupudi, and P.S. Bernstein. (2020). The macular carotenoids: A biochemical overview. Biochim. Biophys. Acta. Mol. Cell Biol. Lipids 1865: 158617. 31931175
Asif, K., L. Memeo, S. Palazzolo, Y. Frión-Herrera, S. Parisi, I. Caligiuri, V. Canzonieri, C. Granchi, T. Tuccinardi, and F. Rizzolio. (2021). STARD3: A Prospective Target for Cancer Therapy. Cancers (Basel) 13:. 34572920
Balboa, E., J. Castro, M.J. Pinochet, G.I. Cancino, N. Matías, P. José Sáez, A. Martínez, A.R. Álvarez, C. Garcia-Ruiz, J.C. Fernandez-Checa, and S. Zanlungo. (2017). MLN64 induces mitochondrial dysfunction associated with increased mitochondrial cholesterol content. Redox Biol 12: 274-284. 28282615
Kennedy, B.E., C.T. Madreiter, N. Vishnu, R. Malli, W.F. Graier, and B. Karten. (2014). Adaptations of energy metabolism associated with increased levels of mitochondrial cholesterol in Niemann-Pick type C1-deficient cells. J. Biol. Chem. 289: 16278-16289. 24790103
Liapis, A., F.W. Chen, J.P. Davies, R. Wang, and Y.A. Ioannou. (2012). MLN64 transport to the late endosome is regulated by binding to 14-3-3 via a non-canonical binding site. PLoS One 7: e34424. 22514632
Miller, W.L. (2013). Steroid hormone synthesis in mitochondria. Mol. Cell Endocrinol 379: 62-73. 23628605
Roth, G.E., M.S. Gierl, L. Vollborn, M. Meise, R. Lintermann, and G. Korge. (2004). The Drosophila gene Start1: a putative cholesterol transporter and key regulator of ecdysteroid synthesis. Proc. Natl. Acad. Sci. USA 101: 1601-1606. 14745013
Soccio, R.E. and J.L. Breslow. (2003). StAR-related lipid transfer (START) proteins: mediators of intracellular lipid metabolism. J. Biol. Chem. 278: 22183-22186. 12724317