Biomedical subjects

Monty Krieger

Publications and source records attributed to Monty Krieger.

At least 19 recordsLinked to original sources

PubMed2007

A new inborn error of glycosylation due to a Cog8 deficiency reveals a critical role for the Cog1-Cog8 interaction in COG complex formation.

The hetero-octameric conserved oligomeric Golgi (COG) complex is essential for the structure/function of the Golgi apparatus through regulation of membrane trafficking. Here, we describe a patient with a mild form of a congenital disorder of glycosylation type II (CDG-II), which is caused by a homozygous nonsense mutation in the hCOG8 gene. This leads to a premature stop codon resulting in a truncated Cog8 subunit lacking the 76 C-terminal amino acids. Mass spectrometric analysis of the N- and O-glycan structures identified a mild sialylation deficiency. We showed that the molecular basis of this defect in N- and O-glycosylation is caused by the disruption of the Cog1-Cog8 interaction due to truncation. As a result, Cog1 deficiency accompanies the Cog8 deficiency, preventing assembly of the intact, stable complex and resulting in the appearance of smaller subcomplexes. Moreover, levels of beta1,4-galactosytransferase were significantly reduced. The defects in O-glycosylation could be fully restored by transfecting the patient's fibroblasts with full-length Cog8. The Cog8 defect described here represents a novel type of CDG-II, which we propose to name as CDG-IIh or CDG caused by Cog8 deficiency (CDG-II/Cog8).

Adaptor Proteins, Vesicular Transport↗

PubMed2006

A dynamic expression survey identifies transcription factors relevant in mouse digestive tract development.

Tissue-restricted transcription factors (TFs), which confer specialized cellular properties, are usually identified through sequence homology or cis-element analysis of lineage-specific genes; conventional modes of mRNA profiling often fail to report non-abundant TF transcripts. We evaluated the dynamic expression during mouse gut organogenesis of 1381 transcripts, covering nearly every known and predicted TF, and documented the expression of approximately 1000 TF genes in gastrointestinal development. Despite distinctive structures and functions, the stomach and intestine exhibit limited differences in TF genes. Among differentially expressed transcripts, a few are virtually restricted to the digestive tract, including Nr2e3, previously regarded as a photoreceptor-specific product. TFs that are enriched in digestive organs commonly serve essential tissue-specific functions, hence justifying a search for other tissue-restricted TFs. Computational data mining and experimental investigation focused interest on a novel homeobox TF, Isx, which appears selectively in gut epithelium and mirrors expression of the intestinal TF Cdx2. Isx-deficient mice carry a specific defect in intestinal gene expression: dysregulation of the high density lipoprotein (HDL) receptor and cholesterol transporter scavenger receptor class B, type I (Scarb1). Thus, integration of developmental gene expression with biological assessment, as described here for TFs, represents a powerful tool to investigate control of tissue differentiation.

Animals↗

PubMed2006

PDZK1 is required for maintaining hepatic scavenger receptor, class B, type I (SR-BI) steady state levels but not its surface localization or function.

PDZK1 is a multi-PDZ domain-containing adaptor protein that binds to the C terminus of the high density lipoprotein receptor, scavenger receptor, class B, type I (SR-BI), and controls the posttranscriptional, tissue-specific expression of this lipoprotein receptor. In the absence of PDZK1 (PDZK1(-/-) mice), murine hepatic SR-BI protein levels are very low (<5% of control). As a consequence, abnormal plasma lipoprotein metabolism ( approximately 1.5-1.7-fold increased total plasma cholesterol carried in both normal size and abnormally large high density lipoprotein particles) resembles, but is not as severely defective as, that in SR-BI(-/-) mice. Here we show that the total plasma cholesterol levels and size distribution of lipoproteins are virtually identical in SR-BI(-/-) and SR-BI(-/-)/PDZK1(-/-) mice, indicating that most, if not all of the effects of PDZK1 on lipoprotein metabolism are likely because of the effects of PDZK1 on SR-BI. Hepatic overexpression of wild-type SR-BI in PDZK1(-/-) mice restored near or greater than normal levels of cell surface-expressed, functional SR-BI protein levels in the livers of SR-BI(-/-)/PDZK1(-/-) mice and consequently restored apparently normal lipoprotein metabolism in the absence of PDZK1. Thus, PDZK1 is important for maintaining adequate steady state levels of SR-BI in the liver but is not essential for cell surface expression or function of hepatic SR-BI.

Animals↗

PubMed2006

IntraGolgi distribution of the Conserved Oligomeric Golgi (COG) complex.

The Conserved Oligomeric Golgi (COG) complex is an eight-subunit (Cog1-8) peripheral Golgi protein involved in membrane trafficking and glycoconjugate synthesis. COG appears to participate in retrograde vesicular transport and is required to maintain normal Golgi structure and function. COG mutations interfere with normal transport, distribution, and/or stability of Golgi proteins associated with glycoconjugate synthesis and trafficking, and lead to failure of spermatogenesis in Drosophila melanogaster, misdirected migration of gonadal distal tip cells in Caenorhabditis elegans, and type II congenital disorders of glycosylation in humans. The mechanism by which COG influences Golgi structure and function is unclear. Immunogold electron microscopy was used to visualize the intraGolgi distribution of a functional, hemagglutinin epitope-labeled COG subunit, Cog1-HA, that complements the Cog1-deficiency in Cog1-null Chinese hamster ovary cells. COG was found to be localized primarily on or in close proximity to the tips and rims of the Golgi's cisternae and their associated vesicles and on vesicles and vesiculo-tubular structures seen on both the cis and trans-Golgi Network faces of the cisternal stacks, in some cases on COPI containing vesicles. These findings support the proposal that COG is directly involved in controlling vesicular retrograde transport of Golgi resident proteins throughout the Golgi apparatus.

Adaptor Proteins, Vesicular Transport↗

PubMed2006

Conserved oligomeric Golgi complex subunit 1 deficiency reveals a previously uncharacterized congenital disorder of glycosylation type II.

The conserved oligomeric Golgi (COG) complex is a heterooctameric complex that regulates intraGolgi trafficking and the integrity of the Golgi compartment in eukaryotic cells. Here, we describe a patient with a mild form of congenital disorder of glycosylation type II (CDG-II) that is caused by a deficiency in the Cog1 subunit of the complex. This patient has a defect in both N- and O-glycosylation. Mass spectrometric analysis of the structures of the N-linked glycans released from glycoproteins from the patient's serum revealed a reduction in sialic acid and galactose residues. Peanut agglutinin (PNA) lectin staining revealed a decrease in sialic acids on core 1 mucin type O-glycans, indicating a combined defect in N- and O-glycosylation. Sequence analysis of the COG1 cDNA and gene identified a homozygous insertion of a single nucleotide (2659-2660insC), which is predicted to lead to a premature translation stop and truncation of the C terminus of the Cog1 protein by 80 amino acids. This mutation destabilizes several other COG subunits and alters their subcellular localization and hence the overall integrity of the COG complex. This results in reduced levels and/or altered Golgi localization of alpha-mannosidase II and beta-1,4 galactosyltransferase I, which links it to the glycosylation deficiency. Transfection of primary fibroblasts of this patient with the full length hemagglutinin-tagged Cog1 indeed restored beta-1,4 galactosyltransferase Golgi localization. We propose naming this disorder CDG-II/Cog1, or CDG-II caused by Cog1 deficiency.

Adaptor Proteins, Vesicular Transport↗

PubMed2006

Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL.

The concentration, composition, shape, and size of plasma high-density lipoprotein (HDL) are determined by numerous proteins that influence its biogenesis, remodeling, and catabolism. The discoveries of the HDL receptor (scavenger receptor class B type I, SR-BI) and the ABCA1 (ATP-binding cassette transporter A1) lipid transporter provided two missing links that were necessary to understand the biogenesis and some of the functions of HDL. Existing data indicate that functional interactions between apoA-I and ABCA1 are necessary for the initial lipidation of apoA-I. Through a series of intermediate steps, lipidated apoA-I proceeds to form discoidal HDL particles that can be converted to spherical particles by the action of lecithin:cholesterol acyltransferase (LCAT). Discoidal and spherical HDL can interact functionally with SR-BI and these interactions lead to selective lipid uptake and net efflux of cholesterol and thus remodel HDL. Defective apoA-I/ABCA1 interactions prevent lipidation of apoA-I that is necessary for the formation of HDL particles. In the same way, specific mutations in apoA-I or LCAT prevent the conversion of discoidal to spherical HDL particles. The interactions of lipid-bound apoA-I with SR-BI are affected in vitro by specific mutations in apoA-I or SR-BI. Furthermore, deficiency of SR-BI affects the lipid and apolipoprotein composition of HDL and is associated with increased susceptibility to atherosclerosis. Here we review the current status of the pathway of HDL biogenesis and mutations in apoA-I, ABCA1, and SR-BI that disrupt different steps of the pathway and may lead to dyslipidemia and atherosclerosis in mouse models. The phenotypes generated in experimental mouse models for apoA-I, ABCA1, LCAT, SR-BI, and other proteins of the HDL pathway may facilitate early diagnosis of similar phenotypes in the human population and provide guidance for proper treatment.

ATP Binding Cassette Transporter 1↗

PubMed2006

Effects of hepatic expression of the high-density lipoprotein receptor SR-BI on lipoprotein metabolism and female fertility.

The etiology of human female infertility is often uncertain. The sterility of high-density lipoprotein (HDL) receptor-negative (SR-BI(-/-)) female mice suggests a link between female infertility and abnormal lipoprotein metabolism. SR-BI(-/-) mice exhibit elevated plasma total cholesterol [with normal-sized and abnormally large HDL and high unesterified to total plasma cholesterol (UC:TC) ratio]. We explored the influence of hepatic SR-BI on female fertility by inducing hepatic SR-BI expression in SR-BI(-/-) animals by adenovirus transduction or stable transgenesis. For transgenes, we used both wild-type SR-BI and a double-point mutant, Q402R/Q418R (SR-BI-RR), which is unable to bind to and mediate lipid transfer from wild-type HDL normally, but retains virtually normal lipid transport activities with low-density lipoprotein. Essentially wild-type levels of hepatic SR-BI expression in SR-BI(-/-) mice restored to nearly normal the HDL size distribution and plasma UC:TC ratio, whereas approximately 7- to 40-fold overexpression dramatically lowered plasma TC and increased biliary cholesterol secretion. In contrast, SR-BI-RR overexpression had little effect on SR-BI(+/+) mice, but in SR-BI(-/-) mice, it substantially reduced levels of abnormally large HDL and normalized the UC:TC ratio. In all cases, hepatic transgenic expression restored female fertility. Overexpression in SR-BI(-/-) mice of lecithin:cholesterol acyl transferase, which esterifies plasma HDL cholesterol, did not normalize the UC:TC ratio, probably because the abnormal HDL was a poor substrate, and did not restore fertility. Thus, hepatic SR-BI-mediated lipoprotein metabolism influences murine female fertility, raising the possibility that dyslipidemia might contribute to human female infertility and that targeting lipoprotein metabolism might complement current assisted reproductive technologies.

Adenoviridae↗

PubMed2006

Retrograde transport on the COG railway.

The conserved oligomeric Golgi (COG) complex is essential for establishing and/or maintaining the structure and function of the Golgi apparatus. The Golgi apparatus, in turn, has a central role in protein sorting and glycosylation within the eukaryotic secretory pathway. As a consequence, COG mutations can give rise to human genetic diseases known as congenital disorders of glycosylation. We review recent results from studies of yeast, worm, fly and mammalian COG that provide evidence that COG might function in retrograde vesicular trafficking within the Golgi apparatus. This hypothesis explains the impact of COG mutations by postulating that they impair the retrograde flow of resident Golgi proteins needed to maintain normal Golgi structure and function.

Adaptor Proteins, Vesicular Transport↗

PubMed2006

Hepatic lipase deficiency delays atherosclerosis, myocardial infarction, and cardiac dysfunction and extends lifespan in SR-BI/apolipoprotein E double knockout mice.

OBJECTIVE: SR-BI/apolipoprotein (apo) E double knockout (dKO) mice exhibit many features of human coronary heart disease (CHD), including occlusive coronary atherosclerosis, cardiac hypertrophy, myocardial infarctions, and premature death. Here we determined the effects on this pathology of hepatic lipase (HL) deficiency, which has been shown to significantly modulate atherosclerosis. METHOD AND RESULTS: The SR-BI/apoE/HL triple knockout (tKO) mice generated for this study lived significantly longer (37%) than corresponding dKO controls (average lifespans: 63.0+/-0.8 versus 46.0+/-0.3 days), despite their increased plasma cholesterol levels. At 6 weeks of age, compared with dKO mice, tKOs exhibited significantly less aortic root and coronary artery occlusive atherosclerosis, and improved cardiac structure and function. However, by 9 weeks of age the hearts of tKO mice exhibited lipid-rich coronary occlusions, myocardial infarctions, and cardiac dysfunction essentially identical to that of 6-week-old dKO mice. CONCLUSIONS: HL-deficiency delays the onset and/or progression of atherosclerosis via a SR-BI-independent mechanism. Extent of occlusive coronary arterial lesions was more closely associated with cardiac dysfunction and lifespan than the amount of aortic root atherosclerosis, suggesting that these occlusions in dKO mice are responsible for ischemia, myocardial infarctions, and premature death.

Age of Onset↗

PubMed2005

SR-BI mediates cholesterol efflux via its interactions with lipid-bound ApoE. Structural mutations in SR-BI diminish cholesterol efflux.

Apolipoprotein E (apoE) and the lipoprotein receptor SR-BI play critical roles in lipid and lipoprotein metabolism. We have examined the cholesterol efflux from wild-type (WT) and mutant forms of SR-BI expressed in ldlA-7 cells using reconstituted discoidal particles consisting of apoE, 1-palmitoyl-2-oleoyl-l-phospatidylcholine (POPC), and cholesterol (C) as acceptors. POPC/C-apoE particles generated using apoE2, apoE3, apoE4, or carboxy-terminally truncated forms apoE4-165, apoE4-202, apoE4-229, and apoE4-259 caused similar (20-25%) cholesterol efflux from WT SR-BI. Cholesterol efflux mediated by POPC/C-apoE was not enhanced in the presence of lipid-free apoE. The rate of cholesterol efflux mediated by particles containing the WT or carboxy-terminally truncated forms of apoE was decreased to approximately 30% of the WT control with the Q402R/Q418R mutant SR-BI form that is unable to bind native HDL normally but binds LDL. The rate of cholesterol efflux was further decreased to approximately 7% of the WT control with another SR-BI mutant (M158R) that binds neither HDL nor LDL. The level of binding of POPC/C-apoE particles (150 microg/mL) to SR-BI mutant forms Q402R/Q418R and M158R was 70 and 8% of the WT control, respectively. SR-BI-dependent binding of lipid-free apoE to cells was undetectable, and cholesterol efflux was less than 0.5%. The findings establish that only lipid-bound apoE promotes SR-BI-mediated cholesterol efflux and that the amino-terminal region of residues 1-165 of apoE is sufficient for both receptor binding and cholesterol efflux. The SR-BI-apoE interactions may contribute to overall cholesterol homeostasis in cells and tissues that express SR-BI and apoE.

Amino Acid Sequence↗

PubMed2005

Genetic analysis of the subunit organization and function of the conserved oligomeric golgi (COG) complex: studies of COG5- and COG7-deficient mammalian cells.

The conserved oligomeric Golgi (COG) complex is an eight-subunit (Cog1-8) peripheral Golgi protein involved in Golgi-associated membrane trafficking and glycoconjugate synthesis. We have analyzed the structure and function of COG using Cog1 or Cog2 null Chinese hamster ovary cell mutants, fibroblasts from a patient with Cog7-deficient congenital disorders of glycosylation, and stable Cog5-deficient HeLa cells generated by RNA interference. Although the dilation of some Golgi cisternae in Cog5-deficient cells resembled that observed in Cog1- or Cog2-deficient cells, their global glycosylation defects (less severe) and intracellular processing and function of low density lipoprotein receptors (essentially normal) differed from Cog1- and Cog2-deficient cells. Immunoblotting, gel filtration, and immunofluorescence microscopy analyses of the COG-deficient cells and cell extracts indicated that 1) Cog2-4 and Cog5-7 form stable subcomplexes, 2) Cog1 mediates Golgi association of a Cog2-4 plus Cog8 subcomplex, 3) Cog8 associates stably with both Cog5-7 and Cog1-4 subcomplexes, and thus 4) Cog8 helps assemble the Cog1-4 and Cog5-7 subcomplexes into the complete COG complex. This model of the subunit organization of COG is in excellent agreement with in vitro data presented in an accompanying paper (Ungar, D., Oka, T., Vasile, E., Krieger, M., and Hughson, F. M. (2005) J. Biol. Chem. 280, 32729-32735). Only one or two of the seven Cog1- or Cog2-dependent Golgi membrane proteins called GEARs are also sensitive to Cog5 or Cog7 deficiency, indicating that the COG subunits play distinctive roles in controlling Golgi structure and function.

Adaptor Proteins, Vesicular Transport↗

PubMed2005

Subunit architecture of the conserved oligomeric Golgi complex.

The conserved oligomeric Golgi (COG) complex is thought to function in intra-Golgi retrograde trafficking mediated by coat protein I vesicles, a pathway essential for the proper structure and function of the Golgi apparatus. Previous work suggested that COG might act as a tethering factor to mediate the initial attachment between coat protein I vesicles and Golgi membranes. Here, we present extensive in vitro co-translation and immunoprecipitation experiments leading to a new model for the overall architecture of the mammalian COG complex. The eight COG subunits (Cog1-8) are found to form two heterotrimeric subassemblies (Cog2/3/4 and Cog5/6/7) linked by a heterodimer composed of the remaining subunits (Cog1/8). This model is in excellent agreement with in vivo data presented in an accompanying paper (Oka, T., Vasile, E., Penman, M., Novina, C. D., Dykxhoorn, D. M., Ungar, D., Hughson, F. M., and Krieger, M. (2005) J. Biol. Chem. 280, 32736-32745).

Adaptor Proteins, Vesicular Transport↗

PubMed2005

Diet-induced occlusive coronary atherosclerosis, myocardial infarction, cardiac dysfunction, and premature death in scavenger receptor class B type I-deficient, hypomorphic apolipoprotein ER61 mice.

BACKGROUND: Normal chow (low fat)-fed mice deficient in both the HDL receptor SR-BI and apolipoprotein E (SR-BI/apoE dKO) provide a distinctive model of coronary heart disease (CHD). They exhibit early-onset hypercholesterolemia characterized by unesterified cholesterol-rich abnormal lipoproteins (lamellar/vesicular and stacked discoidal particles), occlusive coronary atherosclerosis, spontaneous myocardial infarction, cardiac dysfunction, and premature death ( approximately 6 weeks of age). Mice in which similar features of CHD could be induced with a lipid-rich diet would represent a powerful tool to study CHD. METHODS AND RESULTS: To generate a diet-inducible model of CHD, we bred SR-BI-deficient (SR-BI KO) mice with hypomorphic apolipoprotein E mice (ApoeR61(h/h)) that express reduced levels of an apoE4-like murine apoE isoform and exhibit diet-induced hypercholesterolemia. When fed a normal chow diet, SR-BI KO/ApoeR61(h/h) mice did not exhibit early-onset atherosclerosis or CHD; the low expression level of the apoE4-like murine apoE was atheroprotective and cardioprotective. However, when fed an atherogenic diet rich in fat, cholesterol, and cholate, they rapidly developed hypercholesterolemia, atherosclerosis, and CHD, a response strikingly similar to that of SR-BI/apoE dKO mice fed a chow diet, and they died 32+/-6 days (50% mortality) after initiation of the high-fat feeding. CONCLUSIONS: The SR-BI KO/ApoeR61(h/h) mouse is a new model of diet-induced occlusive coronary atherosclerosis and CHD (myocardial infarction, cardiac dysfunction and premature death), allowing control of the age of onset, duration, severity, and possibly regression of disease. Thus, SR-BI KO/ApoeR61(h/h) mice have the potential to contribute to our understanding of CHD and its prevention and treatment.

Animals↗

PubMed2005

Endocytosis is not required for the selective lipid uptake mediated by murine SR-BI.

The scavenger receptor class B, type I (SR-BI) mediates the cellular selective uptake of cholesteryl esters and other lipids from high-density lipoproteins (HDL) and low-density lipoproteins (LDL). This process, unlike classical receptor-mediated endocytosis, does not result in lipoprotein degradation. Instead, the lipid depleted particles are released into the medium. Here we show that selective lipid uptake mediated by murine SR-BI can be uncoupled from the endocytosis of HDL or LDL particles. We found that blocking selective lipid uptake by incubating cells with the small chemical inhibitors BLT-1 or BLT-4 did not affect endocytosis of HDL. Similarly, blocking endocytosis by hyperosmotic sucrose or K+ depletion did not prevent selective lipid uptake from HDL or LDL. These findings suggest that mSR-BI-mediated selective uptake occurs at the cell surface upon the association of lipoproteins with mSR-BI and does not require endocytosis of HDL or LDL particles.

Animals↗

PubMed2005

Mediators of galactose sensitivity in UDP-galactose 4'-epimerase-impaired mammalian cells.

UDP-galactose 4'-epimerase (GALE) catalyzes the final step in the Leloir pathway of galactose metabolism, interconverting UDP-galactose and UDP-glucose. Unlike its Escherichia coli counterpart, mammalian GALE also interconverts UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. Considering the key roles played by all four of these UDP-sugars in glycosylation, human GALE therefore not only contributes to the Leloir pathway, but also functions as a gatekeeper overseeing the ratios of important substrate pools required for the synthesis of glycosylated macromolecules. Defects in human GALE result in the disorder epimerase-deficiency galactosemia. To explore the relationship among GALE activity, substrate specificity, metabolic balance, and galactose sensitivity in mammalian cells, we employed a previously described GALE-null line of Chinese hamster ovary cells, ldlD. Using a transfection protocol, we generated ldlD derivative cell lines that expressed different levels of wild-type human GALE or E. coli GALE and compared the phenotypes and metabolic profiles of these lines cultured in the presence versus absence of galactose. We found that GALE-null cells accumulated abnormally high levels of Gal-1-P and UDP-Gal and abnormally low levels of UDP-Glc and UDP-GlcNAc in the presence of galactose and that human GALE expression corrected each of these defects. Comparing the human GALE- and E. coli GALE-expressing cells, we found that although GALE activity toward both substrates was required to restore metabolic balance, UDP-GalNAc activity was not required for cell proliferation in the presence of otherwise cytostatic concentrations of galactose. Finally, we found that uridine supplementation, which essentially corrected UDP-Glc and, to a lesser extent UDP-GlcNAc depletion, enabled ldlD cells to proliferate in the presence of galactose despite the continued accumulation of Gal-1-P and UDP-Gal. These data offer important insights into the mechanism of galactose sensitivity in epimerase-impaired cells and suggest a potential novel therapy for patients with epimerase-deficiency galactosemia.

Animals↗

PubMed2005

Lymphocytes are not required for the rapid onset of coronary heart disease in scavenger receptor class B type I/apolipoprotein E double knockout mice.

OBJECTIVE: Scavenger receptor class B type I (SR-BI)/apolipoprotein E (apoE) double knockout (dKO) mice exhibit many features of human coronary heart disease (CHD), including occlusive coronary atherosclerosis, cardiac hypertrophy, myocardial infarctions, and premature death. Here we determined the influence of B and T lymphocytes, which can contribute to atherosclerosis, ischemia-reperfusion injury, and cardiomyocyte death, on pathology in dKO mice. METHOD AND RESULTS: The lymphocyte-deficient SR-BI/apoE/recombination activating gene 2 (RAG2) triple knockout mice and corresponding dKO controls generated for this study exhibited essentially identical lipid-rich coronary occlusions, myocardial infarctions, cardiac dysfunction, and premature death (average lifespans 41.6+/-0.6 and 42.0+/-0.5 days, respectively). CONCLUSIONS: B and T lymphocytes and associated immunoglobulin-mediated inflammation are not essential for the development and progression of CHD in dKO mice. Strikingly, the dKO mice bred for this study (mixed C57BL/6xSV129xBALB/c background; strain 2) compared with the previously described dKO mice (75:25 C57BL/6:SV129 background; strain 1) had a shorter mean lifespan and steeper survival curve, characteristics especially attractive for studying the effects of environmental, pharmacological, and genetic manipulations on cardiac pathophysiology.

Animals↗

PubMed2005

Multi-component protein complexes and Golgi membrane trafficking.

Several large cytosolic protein complexes with multiple components have been proposed to play key roles in mediating or controlling membrane trafficking. Among these complexes, TRAPP, COG and GARP/VFT have been implicated in multiple steps of Golgi membrane trafficking. The importance of these complexes for Golgi function has been established using in vitro biochemical assays and yeast and mammalian somatic cell genetics. Furthermore, mutations in the genes encoding subunits of either TRAPP or the COG complex have been shown to be responsible for human genetic disorders. We here review recent studies exploring the structures and functions of these three oligomeric complexes.

Animals↗

PubMed2005

Regulation of SR-BI-mediated high-density lipoprotein metabolism by the tissue-specific adaptor protein PDZK1.

PURPOSE OF REVIEW: A novel mechanism for the regulation of lipoprotein receptor activity is providing new insights into the control of lipid metabolism. The tissue-specific adaptors ARH (autosomal recessive hypercholesterolemia) and PDZK1 [where PDZ derives from postsynaptic density protein (PSD-95)/Drosophila discs-large (dlg)/tight-junction protein (ZO1)] have been shown to control the activities of distinct types of lipoprotein receptors in a posttranscriptional fashion, significantly affecting overall lipoprotein metabolism. This review will focus on one of these lipoprotein receptor-adaptor pairs, the high-density lipoprotein receptor SR-BI (scavenger receptor class B, type I) and its adaptor PDZK1. RECENT FINDINGS: The PDZ domain-containing adaptor protein PDZK1 has been shown to bind to and control the activity of the high-density lipoprotein receptor SR-BI via a tissue-specific posttranscriptional mechanism. Mice deficient in PDZK1 have elevated plasma cholesterol levels due to the virtually complete hepatic ablation of SR-BI, implicating PDZK1 as a novel regulator of high-density lipoprotein metabolism. SUMMARY: The functions of ARH and PDZK1 suggest that other adaptor proteins may be found to control the activities of other cell-surface receptors in a similar tissue-specific fashion. Manipulation of the expression and/or activities of such adaptors might provide new insights into receptor physiology and these adaptors may prove to be attractive targets for pharmaceutical intervention in cholesterol metabolism-related disease processes.

Adaptor Proteins, Signal Transducing↗