The cholesterol-regulated StarD4 gene encodes a StAR-related lipid transfer protein with two closely related homologues, StarD5 and StarD6

Abstract

Using cDNA microarrays, we identified StarD4 as a gene whose expression decreased more than 2-fold in the livers of mice fed a high-cholesterol diet. StarD4 expression in cultured 3T3 cells was also sterol-regulated, and known sterol regulatory element binding protein (SREBP)-target genes showed coordinate regulation. The closest homologues to StarD4 were two other StAR-related lipid transfer (START) proteins named StarD5 and StarD6. StarD4, StarD5, and StarD6 are 205-to 233-aa proteins consisting almost entirely of START domains. These three constitute a subfamily among START proteins, sharing Ϸ30% amino acid identity with one another, Ϸ20% identity with the cholesterol-binding START domains of StAR and MLN64, and less than 15% identity with phosphatidylcholine transfer protein (PCTP) and other START domains. StarD4 and StarD5 were expressed in most tissues, with highest levels in liver and kidney, whereas StarD6 was expressed exclusively in the testis. In contrast to StarD4, expression of StarD5 and MLN64 was not sterol-regulated. StarD4, StarD5, and StarD6 may be involved in the intracellular transport of sterols or other lipids.

Crystal structure of the Mus musculus cholesterol-regulated START protein 4 (StarD4) containing a StAR-related lipid transfer domain

“…START domain sequences were grouped into nine distinct subfamilies (naming reflects sequence features N-terminal to the START domain): StarD4-like proteins, MLN64͞StAR, RhoGAP, HD-Zip, PCTP-like proteins divided into three subgroups, Goodpasture antigen-binding proteins (GABP), acyl-CoA thioester hydrolases (ACH), A. thaliana membrane-related proteins (MRP), and plant pleckstrin homology (PH) proteins divided into two subgroups. A subset of these subfamilies is found in the human genome (11). The StarD4 subfamily includes StarD4, StarD5, and StarD6, which are Ϸ30% identical to each other.…”

“…In this paper, we report the crystal structure of the mouse cholesterol-regulated START protein 4 (StarD4), which shares a 21% sequence identity with human MLN64 (11). This second START domain structure permitted a useful comparison with the structure of MLN64 (8).…”

Comparative genomics of insect juvenile hormone biosynthesis☆

“…DNA microarray analysis of genes downregulated by dietary cholesterol in mice (Soccio et al, 2002) revealed that only a subset of the isoprenoid pathway enzymes were affected significantly at the transcriptional level, namely HMG-CoA synthase, IPP isomerase and the prenyl transferase FPPS, of which we now have molecular probes. Similarly, DNA microarray analysis showed that mevalonate kinase is the enzyme most affected by sterol regulatory element binding proteins (Horton et al, 2003).…”

A pH-dependent Molten Globule Transition Is Required for Activity of the Steroidogenic Acute Regulatory Protein, StAR

“…Models of StAR show the same fold (12,14,15), suggesting action as a transport protein. Recent data suggest that members of the StarD4 family of related proteins, which lack mitochondrial targeting sequences, serve as cytosolic transporters for insoluble lipid molecules (16,17). Furthermore, one molecule of StAR apparently facilitates the mitochondrial import of about 400 molecules of cholesterol (18), suggesting a similar mechanism for StAR action.…”