Modeling the structure of the StART domains of MLN64 and StAR proteins in complex with cholesterol

Murcia, Marta; Faraldo‐Gómez, José D.; Maxfield, Frederick R.; Roux, Benoı̂t

doi:10.1194/jlr.m600232-jlr200

Cited by 106 publications

(139 citation statements)

References 109 publications

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“…Modeling indicates that N-216 MLN64 accommodates a single molecule of cholesterol in this pocket, with the 3 ␤ -OH group coordinated by the two polar residues at the bottom of the pocket. This structure, the crystal structure of the closely related protein StarD4 ( 208 ), and several computational models of StAR (209)(210)(211) are all very similar. Each is characterized by two long ␣ -helixes at the N-and C-termini, two short ␣ -helixes, and a set of nine antiparallel ␤ sheets that form a helix-grip fold ( Fig.…”

Section: Acute Versus Chronic Regulation Ofmentioning

confidence: 76%

Early steps in steroidogenesis: intracellular cholesterol trafficking

Miller

Bose

2011

Journal of Lipid Research

457

398

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Section: Acute Versus Chronic Regulation Ofmentioning

confidence: 76%

Early steps in steroidogenesis: intracellular cholesterol trafficking

Miller

Bose

2011

Journal of Lipid Research

457

398

View full text Add to dashboard Cite

“…Of particular interest is the observation that genetic ablation of mouse LAMPI and LAMPII, which are both AP-3 cargoes (Bonifacino and Traub, 2003), alters the cellular content of cholesterol detected by filipin staining (Eskelinen et al, 2004). Alternatively, other proteins, such as MLN64, a membrane protein targeted to late endosomes that is predicted to bind cholesterol, based upon structural studies (Alpy et al, 2001;Murcia et al, 2006), could contribute to the phenotypes observed in AP-3 -/-cells. Irrespective of the precise mechanism that leads to reduced cellular cholesterol levels, targeted perturbation of AP-3 complex function might help ameliorate cholesterol accumulation defects seen in a number of disorders, including in NP-C.…”

Section: Journal Of Cell Science 120 (20)mentioning

confidence: 99%

The subcellular localization of the Niemann-Pick Type C proteins depends on the adaptor complex AP-3

Berger

Salazar

Styers

et al. 2007

Journal of Cell Science

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Niemann-Pick Type C (NP-C) disease, caused by mutations in either human NPC1 (hNPC1) or human NPC2 (hNPC2), is characterized by the accumulation of unesterified cholesterol in late endosomes. Although it is known that the NP-C proteins are targeted to late endosomal/lysosomal compartments, their delivery mechanisms have not been fully elucidated. To identify mechanisms regulating NP-C protein localization, we used Saccharomyces cerevisiae, which expresses functional homologs of both NP-C proteins – scNcr1p and scNpc2p. Targeting of scNcr1p to the vacuole was perturbed in AP-3-deficient yeast cells, whereas the delivery of scNpc2p was affected by deficiencies in either AP-3 or GGA. We focused on the role of the AP-3 pathway in the targeting of the mammalian NP-C proteins. We found that, although mouse NPC1 (mNPC1) and hNPC2 co-localize with AP-3 to a similar extent in fibroblasts, hNPC2 preferentially co-localizes with AP-1. Importantly, the targeting of both mammalian NPC1 and NPC2 is dependent on AP-3. Moreover, and consistent with the NP-C proteins playing a role in cholesterol metabolism, AP-3-deficient cells have reduced levels of cholesterol. These results provide information about how the NP-C proteins are targeted to their sites of action and illustrate the possibility that defective sorting of the NP-C proteins along the endocytic route can alter cellular cholesterol.

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“…The crystal structure of PCTP/StarD2 also shows a hydrophobic tunnel, but in contrast to MLN64/StarD3 and StarD4, it appears to selectively bind phosphatidylcholine (15). More recent modeling studies of the structure of StarD1 and MLN64 have shown that cholesterol appears to be bound by the predicted hydrophobic tunnel of both proteins and reveals changes in the loop at the entrance of the hydrophobic tunnel that may be sufficient for the uptake and release of cholesterol (16).…”

mentioning

confidence: 99%

Intracellular cholesterol transporter StarD4 binds free cholesterol and increases cholesteryl ester formation

Rodríguez‐Agudo

Ren

Wong

et al. 2008

Journal of Lipid Research

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StarD4 protein is a member of the StarD4 subfamily of steroidogenic acute regulatory-related lipid transfer (START) domain proteins that includes StarD5 and StarD6, proteins whose functions remain poorly defined. The objective of this study was to isolate and characterize StarD4ʼs sterol binding and to determine in a hepatocyte culture model its sterol transport capabilities. Cholesterol is a structural component of mammalian cell membranes and also serves as a precursor to bile acids (in the liver), steroid hormones (in the adrenal, testis, and ovaries), and vitamin D. Homeostasis of cholesterol within the body is maintained through the coordinated regulation of its cell-mediated uptake, transport/trafficking, sorting, biosynthesis, storage (i.e., esterification), secretion, and catabolism to bile acids (1). More specifically, the steroidogenic acute regulatory-related lipid transfer (START) domain superfamily of proteins has been shown to be involved in several pathways of intracellular trafficking of cholesterol (2-4). It has been predicted that all proteins with a START domain contain a similar binding pocket with modifications in that pocket that determine ligand binding specificity and function (5). The START domains are 200-210 amino acid motifs that appear in a wide range of proteins and have been implicated in several cellular functions, including lipid transport and metabolism, signal transduction, and transcriptional regulation (3, 4, 6). The START-related lipid transfer protein 4 (StarD4) belongs to the StarD4 subfamily, a START subfamily that also contains the proteins StarD5 and StarD6. The proteins in the StarD4 subfamily have been shown to contain 205-233 amino acid residues, sharing 26-32% identity with each other (7). Within the StarD4 subfamily, StarD5 has been shown in vitro to bind cholesterol and 25-hydroxycholesterol (4). StarD1 and MLN64/StarD3 (the nearest related proteins to the StarD4 subfamily) have been shown to bind only cholesterol (4,8). Furthermore, full-length StarD1, StarD4, StarD5 and truncated MLN64/StarD3 have been reported to increase steroidogenesis and/or increase free cholesterol in the microsomes after overexpression in cell culture, representative evidence of their ability to transfer cholesterol (4, 9-12).The first START domain protein crystal structure reported was the C-terminal portion of human MLN64/ StarD3 (8), followed subsequently by the structure of mouse StarD4 (13). The protein structures of MLN64/ StarD3 and StarD4 revealed similar secondary structural elements and a hydrophobic tunnel with a size consistent with the binding of one cholesterol molecule (8, 13). Less

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Modeling the structure of the StART domains of MLN64 and StAR proteins in complex with cholesterol

Cited by 106 publications

References 109 publications

Early steps in steroidogenesis: intracellular cholesterol trafficking

Early steps in steroidogenesis: intracellular cholesterol trafficking

The subcellular localization of the Niemann-Pick Type C proteins depends on the adaptor complex AP-3

Intracellular cholesterol transporter StarD4 binds free cholesterol and increases cholesteryl ester formation

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