9.B.64 The Putative Cholesterol Transporter (Start1) Family
Two members of the Start1/MLN64 family are partially characterized. The human metastatic lymph node 64 (MLN64) protein, a putative 4 TMS protein, where residues 52-170 in this 445 aa protein are transmembrane, and the Drosophila melanogaster Start1 protein, a putative 4 TMS protein where residues 62-183 in this 583 aa protein are transmembrane. Roth et al. (2004) have proposed that Start1 is a cholesterol transporter. This Drosophila protein shows slight sequence similarity with melastatin1 (TC #1.A.4.5.2) (BLAST score of 0.005; 20% identity; 39% similarity; 15% gaps) where residues 164-475 in Start1 aligns with residues 995-1314 in melastatin1. Melastatin1 is a member of the TRP-CC Family (TC #1.A.4).
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) suggest that Start1 plays a role in the regulation of ecdysteroid synthesis, and expression of Start1 depends on ecdysone. These authors suggest 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.
STAR-related lipid transfer (START) domains are ~210 aa lipid binding domains implicated in intracellular lipid transport, lipid metabolism and cell signaling (Soccio and Breslow, 2003). The prototype is the steroidogenic acute regulatory (StAR) protein which transfers cholesterol to mitochondria in steroid hormone-producing cells. 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).