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

Romanowski, M.J.; Soccio, Raymond E.; Breslow, Jan L.; Burley, S.K.

doi:10.1073/pnas.052140699

Cited by 156 publications

(159 citation statements)

References 31 publications

Supporting

Mentioning

152

Contrasting

Order By: Relevance

“…The consequent reduction of cholesterol in virions was associated with a significant decrease in viral infectivity. Similar cholesterol-binding sites have been identified in several membrane proteins, which include the mitochondrial p-benzodiazepine receptor protein (37), caveolin (29), and steroid acute regulatory protein 4 (38). In each case, the direct binding of cholesterol or a sterol analog to the CRM (V͞Lx 2-4 Yx 1-4 R͞K) was demonstrated, where x is a neutral or negatively charged amino acid.…”

Section: Discussionmentioning

confidence: 53%

Nef increases the synthesis of and transports cholesterol to lipid rafts and HIV-1 progeny virions

Zheng

Plemenitaš

Fielding

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

160

169

View full text Add to dashboard Cite

HIV buds from lipid rafts and requires cholesterol for its egress from and entry into cells. Viral accessory protein Nef plays a major role in this process. In this study, it not only increased the biosynthesis of lipid rafts and viral particles with newly synthesized cholesterol, but also enriched them. Furthermore, via the consensus cholesterol recognition motif at its C terminus, Nef bound cholesterol. When this sequence was mutated, Nef became unable to transport newly synthesized cholesterol into lipid rafts and viral particles. Interestingly, although its levels in lipid rafts were not affected, this mutant Nef protein was poorly incorporated into viral particles, and viral infectivity decreased dramatically. Thus, Nef also transports newly synthesized cholesterol to the site of viral budding. As such, it provides essential building blocks for the formation of viruses that replicate optimally in the host.T he negative effector (Nef) protein from human and simian immunodeficiency viruses is a membrane-associated myristoylated protein that measures 27-35 kDa (1-3). It is critical for high levels of viremia and the progression to AIDS in infected humans (4) and monkeys (5). This phenotype has been correlated with increased viral infectivity in vitro, which provides a convenient assay to study its effects in cultured cells (6, 7). This infectivity enhancement can be dependent on or independent of CD4 that serves as the receptor for viral entry. In the former case, Nef decreases the expression of CD4 on the cell surface, thereby increasing the incorporation of viral envelope (Env) proteins into virions (8). In the latter case, Nef still increases viral infectivity significantly (9, 10). This enhancement cannot be complemented by the expression of Nef in target cells. Although no differences were identified in major structural components and morphology between wild-type and mutant virions that lack Nef, ⌬Nef viruses displayed less efficient reverse transcription in target cells. Because Nef is expressed abundantly at the earliest stages of the viral replicative cycle (11), Nef could affect viral morphogenesis and budding to increase the fitness of the virus and facilitate its entry into recipient cells.Lipid rafts, also known as detergent-resistant membranes (DRMs), are microdomains in the plasma membrane that are enriched in sphingolipids, cholesterol, and a subset of cellular proteins (12, 13). Two major pathways contribute to cholesterol homeostasis in mammalian cells (14). Most exogenous cholesterol, which originates from low-density lipoproteins, is internalized via coated pits and distributed to intracellular pools. In addition, cells can synthesize cholesterol in their endoplasmic reticulum when the uptake of exogenous cholesterol is blocked. The newly synthesized cholesterol is then transported into the Golgi apparatus and distributed to various intracellular pools. Because cellular cholesterol is compartmentalized, some sites (including DRMs) are enriched in this newly synthesized lipid (15,16).Previous...

show abstract

Section: Discussionmentioning

confidence: 53%

Nef increases the synthesis of and transports cholesterol to lipid rafts and HIV-1 progeny virions

Zheng

Plemenitaš

Fielding

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

160

169

View full text Add to dashboard Cite

show abstract

“…Second, these three proteins are most homologous to StAR and MLN64, which bind cholesterol, and more distantly related to PCTP and other START domains, which bind phospholipids and perhaps other lipids. Third, the crystal structure of StarD4 shows a hydrophobic tunnel with dimensions similar to those of MLN64 (13). StarD4, StarD5, and StarD6 may be cytosolic lipid carriers like PCTP (16), since all four lack additional N-terminal domains or other localization signals [based on PROSITE searches (17)].…”

Section: Discussionmentioning

confidence: 99%

“…The other four subfamilies were proteins with PCTP-like START domains, proteins with N-terminal Rho GTPase activator protein (RhoGAP) domains, proteins with N-terminal acyl-CoA hydrolase (ACH) domains, and the hypothetical protein KIAA1300. Additional subfamilies of START proteins are present only in plants (13).…”

Section: Sterol Regulation Of Stard4 Expression In Vivo and In Vitromentioning

confidence: 99%

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

Soccio

Adams

Romanowski

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

174

162

View full text Add to dashboard Cite

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.

show abstract

“…Proteins of the steroidogenic acute regulatory (StAR) family play a major role in steroid hormone synthesis by selectively transporting Ch to and into Mito (3, 6 -8). These proteins contain a C-terminal segment of ϳ200 amino acids, the StAR-related lipid transfer (START) domain, which binds a single Ch molecule in highly selective fashion (9,10). StarD1, the family prototype, localizes in the Mito outer membrane (OM), and in conjunction with peripheral benzodiazepine receptor and other proteins (3,7,11), facilitates the translocation of incoming Ch to the inner membrane (IM) for processing by the P450scc system (2,3).…”

mentioning

confidence: 99%

Deleterious Cholesterol Hydroperoxide Trafficking in Steroidogenic Acute Regulatory (StAR) Protein-expressing MA-10 Leydig Cells

Korytowski

Piłat

Schmitt

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: StAR proteins in steroidogenic cells transport cholesterol to/into mitochondria. Under oxidative stress, StARs might deliver damaging cholesterol hydroperoxides (ChOOHs). Results: Steroidogenic activation of MA-10 Leydig cells results in StarD1/D4 expression, ChOOH delivery to mitochondria, membrane potential loss, and reduced progesterone output. Conclusion: Activated cells are susceptible to mitochondrial damage/dysfunction by ChOOHs. Significance: Novel insights into how steroidogenic tissues can be damaged under oxidative stress are provided.

show abstract

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

Cited by 156 publications

References 31 publications

Nef increases the synthesis of and transports cholesterol to lipid rafts and HIV-1 progeny virions

Nef increases the synthesis of and transports cholesterol to lipid rafts and HIV-1 progeny virions

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

Deleterious Cholesterol Hydroperoxide Trafficking in Steroidogenic Acute Regulatory (StAR) Protein-expressing MA-10 Leydig Cells

Contact Info

Product

Resources

About