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1.
Oxysterol-binding protein/OSBP-related proteins (ORPs) constitute a conserved family of sterol/phospholipid-binding proteins with lipid transporter or sensor functions. We investigated the spatial occurrence and regulation of the interactions of human OSBP/ORPs or the S. cerevisiae orthologs, the Osh (OSBP homolog) proteins, with their endoplasmic reticulum (ER) anchors, the VAMP-associated proteins (VAPs), by employing bimolecular fluorescence complementation and pull-down set-ups. The ORP–VAP interactions localize frequently at distinct subcellular sites, shown in several cases to represent membrane contact sites (MCSs). Using established ORP ligand-binding domain mutants and pull-down assays with recombinant proteins, we show that ORP liganding regulates the ORP–VAP association, alters the subcellular targeting of ORP–VAP complexes, or modifies organelle morphology. There is distinct protein specificity in the effects of the mutants on subcellular targeting of ORP–VAP complexes. We provide evidence that complexes of human ORP2 and VAPs at ER–lipid droplet interfaces regulate the hydrolysis of triglycerides and lipid droplet turnover. The data suggest evolutionarily conserved, complex ligand-dependent functions of ORP–VAP complexes at MCSs, with implications for cellular lipid homeostasis and signaling. 相似文献
2.
Antonietta Pietrangelo Neale D. Ridgway 《Cellular and molecular life sciences : CMLS》2018,75(17):3079-3098
Oxysterol-binding protein (OSBP) and OSBP-related proteins (ORPs) constitute a large eukaryotic gene family that transports and regulates the metabolism of sterols and phospholipids. The original classification of the family based on oxysterol-binding activity belies the complex dual lipid-binding specificity of the conserved OSBP homology domain (OHD). Additional protein- and membrane-interacting modules mediate the targeting of select OSBP/ORPs to membrane contact sites between organelles, thus positioning the OHD between opposing membranes for lipid transfer and metabolic regulation. This unique subcellular location, coupled with diverse ligand preferences and tissue distribution, has identified OSBP/ORPs as key arbiters of membrane composition and function. Here, we will review how molecular models of OSBP/ORP-mediated intracellular lipid transport and regulation at membrane contact sites relate to their emerging roles in cellular and organismal functions. 相似文献
3.
Signal regulation by family conspiracy 总被引:6,自引:0,他引:6
The signal regulating proteins (SIRPs) are a family of ubiquitously expressed transmembrane glycoproteins composed of two
subgroups: SIRPα and SIRPβ, containing more than ten members. SIRPα has been shown to inhibit signalling through a variety of receptors including receptor tyrosine kinases and cytokine receptors.
This function involves protein tyrosine kinases and is dependent on immunoreceptor tyrosine-based inhibition motifs which
recruit key protein tyrosine phosphatases to the membrane. Negative regulation by SIRPα may also involve its ligand, CD47, in a bi-directional signalling mechanism. The SIRPβ subtype has no cytoplasmic domain but instead associates with at least one other transmembrane protein (DAP-12, or KARAP).
DAP-12 possesses immunoreceptor tyrosine-based activation motifs within its cytoplasmic domain that are thought to link SIRPβ to activating machinery. SIRPα and SIRPβ thus have complementary roles in signal regulation and may conspire to tune the response to a stimulus.
Received 6 July 2000; revised 2 August 2000; accepted 5 August 2000 相似文献
4.
Viero G Gropuzzo A Joubert O Keller D Prévost G Dalla Serra M 《Cellular and molecular life sciences : CMLS》2008,65(2):312-323
γ-Hemolysins are pore-forming toxins which develop from water-soluble monomers by combining two different ‘albeit homologous’
proteins. They form oligomeric pores in both cell and model membranes by undergoing a still poorly understood conformational
rearrangement in the stem region. The stem is formed by three β-strands, folded onto the core of the soluble protein and completely
extended in the pore. We propose a new model to explain such a process. Seven double-cysteine mutants were developed by inserting
one cysteine on the stretch that links the β-hairpin to the core of the protein and another on different positions along the
β-strands. The membrane bound protein was blocked in a non-lytic state by S–S bond formation. Six mutants were oxidized as
inactive intermediates, but became active after adding DTT. These results demonstrate that the stem extension can be temporarily
frozen and that the β-barrel formation occurs by β-strand concerted step-by-step sliding.
Received 22 October 2007; received after revision 15 November 2007; accepted 19 November 2007 相似文献
5.
Bruno Mesmin Bruno Antonny Guillaume Drin 《Cellular and molecular life sciences : CMLS》2013,70(18):3405-3421
In cells, the levels of sterol vary greatly among organelles. This uneven distribution depends largely on non-vesicular routes of transfer, which are mediated by soluble carriers called lipid-transfer proteins (LTPs). These proteins have a domain with a hydrophobic cavity that accommodates one sterol molecule. However, a demonstration of their role in sterol transport in cells remains difficult. Numerous LTPs also contain membrane-binding elements, but it is not clear how these LTPs couple their ability to target organelles with lipid transport activity. This issue appears critical, since many sterol transporters are thought to act at contact sites between two membrane-bound compartments. Here, we emphasize that biochemical and structural studies provide precious insights into the mode of action of sterol-binding proteins. Recent studies on START, Osh/ORP and NPC proteins suggest models on how these proteins could transport sterol between organelles and, thereby, influence cellular functions. 相似文献
6.
The V(D)J recombination activating protein RAG2 consists of a six-bladed propeller and a PHD fingerlike domain, as revealed by sequence analysis 总被引:3,自引:0,他引:3
The RAG1 and RAG2 proteins play a crucial role in V(D)J recombination by cooperating to make specific double-stranded DNA
breaks at a pair of recombination signal sequences (RSSs). However, the exact function they perform has heretofore remained
elusive. Using a combination of sensitive methods of sequence analysis, we show here that the active core region of the RAG2
protein, confined to the first three quarters of its sequence, is in fact composed of a six-fold repeat of a 50-residue motif
which is related to the kelch/mipp motif. This motif, which forms a four-stranded twisted antiparallel β sheet, is arranged in a circular formation like blades of a propeller or turbine. Given the known properties of the β-propeller fold in mediating protein-protein interactions, it is proposed that this six-laded propeller structure of the RAG2
active core would play a crucial role in the tight complex formed by the RAG1 and RAG2 proteins and RSSs. Moreover, the presence
of a plant homeodomain finger-like motif in the last quarter of the RAG2 sequence suggests a potential interaction of this
domain with chromatin components.
Received 6 June 1998; accepted 9 June 1998 相似文献
7.
MurNAc etherases cleave the uniqued-lactyl ether bond of the bacterial cell wall sugar N-acetylmuramic acid (MurNAc). Members of this newly discovered family of enzymes are widely distributed among bacteria and
are required to utilize peptidoglycan fragments obtained either from the environment or from the endogenous cell wall (i.e.,
recycling). MurNAc etherases are strictly dependent on the substrate MurNAc possessing a free reducing end and a phosphoryl
group at C6. They carry a single conserved sugar phosphate isomerase/sugar phosphate- binding (SIS) domain to which MurNAc
6-phosphate is bound. Two subunits form an enzymatically active homodimer that structurally resembles the isomerase module
of the double-SIS domain protein GlmS, the glucosamine 6-phosphate synthase. Structural comparison provides insights into
the two-step lyase-type reaction mechanism of MurNAc etherases: β-elimination of the D-lactic acid substituent proceeds through
a 2,3-unsaturated sugar intermediate to which water is subsequently added.
Received 31 August 2007; received after revision 12 October 2007; accepted 1 November 2007 相似文献
8.
4-Hydroxynonenal-modified amyloid-beta peptide inhibits the proteasome: possible importance in Alzheimer's disease 总被引:3,自引:0,他引:3
Shringarpure R Grune T Sitte N Davies KJ 《Cellular and molecular life sciences : CMLS》2000,57(12):1802-1809
The amyloid β-peptide (Aβ) is a 4-kDa species derived from the amyloid precursor protein, which accumulates in the brains of patients with Alzheimer’s
disease. Although we lack full understanding of the etiology and pathogenesis of selective neuron death, considerable data
do imply roles for both the toxic Aβ and increased oxidative stress. Another significant observation is the accumulation of abnormal, ubiquitin-conjugated proteins
in affected neurons, suggesting dysfunction of the proteasome proteolytic system in these cells. Recent reports have indicated
that Aβ can bind and inhibit the proteasome, the major cytoslic protease for degrading damaged and ubiquitin-conjugated proteins.
Earlier results from our laboratory showed that moderately oxidized proteins are preferentially recognized and degraded by
the proteasome; however, severely oxidized proteins cannot be easily degraded and, instead, inhibit the proteasome. We hypothesized
that oxidatively modified Aβ might have a stronger (or weaker) inhibitory effect on the proteasome than does native Aβ. We therefore also investigated the proteasome inhibitory action of Aβ
1–40 (a peptide comprising the first 40 residues of Aβ) modified by the intracellular oxidant hydrogen peroxide, and by the lipid peroxidation product 4-hydroxynonenal (HNE). H2O2 modification of Aβ
1–40 generates a progressively poorer inhibitor of the purified human 20S proteasome. In contrast, HNE modification of Aβ
1–40 generates a progressively more selective and efficient inhibitor of the degradation of fluorogenic peptides and oxidized
protein substrates by human 20S proteasome. This interaction may contribute to certain pathological manifestations of Alzheimer’s
disease
Received 26 September 2000; accepted 26 September 2000 相似文献
9.
Retinal proteins function as photoreceptors and ion pumps. Xanthorhodopsin of Salinibacter ruber is a recent addition to this diverse family. Its novel and distinctive feature is a second chromophore, a carotenoid, which
serves as light-harvesting antenna. Here we discuss the properties of this carotenoid/retinal complex most relevant to its
function (such as the specific binding site controlled by the retinal) and its relationship to other retinal proteins (bacteriorhodopsin,
archaerhodopsin, proteorhodopsin and retinal photoreceptors of archaea and eukaryotes). Antenna addition to a retinal protein
has not been observed among the archaea and emerged in bacteria apparently in response to environmental conditions where light-harvesting
becomes a limiting factor in retinal protein functioning.
Received 2 April 2007; received after revision 14 May 2007; accepted 16 May 2007 相似文献
10.
Peroxisomes metabolize a variety of lipids, acting as a chain-shortening system that produces
acyl-CoAs of varying chain lengths, including acetyl-CoA and propionyl-CoA. It is, however, still largely
unknown how β-oxidation products exit peroxisomes and where they are further metabolized. Peroxisomes
contain carnitine acetyltransferase (CRAT) and carnitine octanoyltransferase (CROT) that produce carnitine esters for transport
out of peroxisomes, together with recently characterized acyl-CoA thioesterases (ACOTs) that produce free fatty acids. Here
we have performed tissue expression profiling of the short- and medium-chain carnitine acyltransferases Crat, Crot and the short- and medium-chain thioesterases (Acot12) and (Acot5), and show that they are largely expressed in different tissues, suggesting that they do not compete for the same substrates
but rather provide complementary systems for transport of metabolites across the peroxisomal membrane. These data also explain
earlier observed tissue differences in peroxisomal production of acetyl-CoA/acetyl-carnitine/acetate and underscores the differences
in peroxisome function in various organs.
Received 18 December 2007; received after revision 18 January 2008; accepted 22 January 2008 相似文献
11.
Site- and state-specific lysine methylation of histones is catalyzed by a family of proteins that contain the evolutionarily
conserved SET domain and plays a fundamental role in epigenetic regulation of gene activation and silencing in all eukaryotes.
The recently determined three-dimensional structures of the SET domains from chromosomal proteins reveal that the core SET
domain structure contains a two-domain architecture, consisting of a conserved anti-parallel β-barrel and a structurally variable
insert that surround a unusual knot-like structure that comprises the enzyme active site. These structures of the SET domains,
either in the free state or when bound to cofactor S-adenosyl-L-homocysteine and/or histone peptide, mimicking an enzyme/cofactor/substrate complex, further yield the structural insights
into the molecular basis of the substrate specificity, methylation multiplicity and the catalytic mechanism of histone lysine
methylation.
Received 10 June 2006; accepted 22 August 2006 相似文献
12.
Izaurralde E 《Cellular and molecular life sciences : CMLS》2001,58(8):1105-1112
The distinguishing feature of eukaryotic cells is the segregation of RNA biogenesis and DNA replication in the nucleus, separate
from the cytoplasmic machinery for protein synthesis. As a consequence, messenger RNAs (mRNAs) and all cytoplasmic RNAs from
nuclear origin need to be transported from their site of synthesis in the nucleus to their final cytoplasmic destination.
Nuclear export occurs through nuclear pore complexes (NPCs) and is mediated by saturable transport receptors, which shuttle
between the nucleus and cytoplasm. The past years have seen great progress in the characterization of the mRNA export pathway
and the identification of proteins involved in this process. A novel family of nuclear export receptors (the NXF family),
distinct from the well-characterized family of importin β-like proteins, has been implicated in the export of mRNA to the cytoplasm.
Received 23 January 2001; received after revision 12 April 2001; accepted 12 April 2001 相似文献
13.
Terhi Vihervaara Riikka-Liisa Uronen Gerd Wohlfahrt Ingemar Björkhem Elina Ikonen Vesa M. Olkkonen 《Cellular and molecular life sciences : CMLS》2011,68(3):537-551
ORP1L is an oxysterol binding homologue that regulates late endosome (LE) positioning. We show that ORP1L binds several oxysterols
and cholesterol, and characterize a mutant, ORP1L Δ560–563, defective in oxysterol binding. While wild-type ORP1L clusters
LE, ORP1L Δ560–563 induces LE scattering, which is reversed by disruption of the endoplasmic reticulum (ER) targeting FFAT
motif, suggesting that it is due to enhanced LE–ER interactions. Endosome motility is reduced upon overexpression of ORP1L.
Both wild-type ORP1L and the Δ560–563 mutant induce the recruitment of both dynactin and kinesin-2 on LE. Most of the LE decorated
by overexpressed ORP1L fail to accept endocytosed dextran or EGF, and the transfected cells display defective degradation
of internalized EGF. ORP1L silencing in macrophage foam cells enhances endosome motility and results in inhibition of [3H]cholesterol efflux to apolipoprotein A-I. These data demonstrate that LE motility and functions in both protein and lipid
transport are regulated by ORP1L. 相似文献
14.
Kraft B Johswich A Kauczor G Scharenberg M Gerardy-Schahn R Bakker H 《Cellular and molecular life sciences : CMLS》2011,68(24):4091-4100
The glycolipid specific Drosophila melanogaster β1,4-N-acetylgalactosaminyltransferase B (β4GalNAcTB) depends on a zinc finger DHHC protein family member named GalNAcTB pilot (GABPI)
for activity and translocation to the Golgi. The six-membrane spanning protein actually lacks the cysteine in the cytoplasmic
DHHC motif, displaying DHHS instead. Here we show that the whole conserved region around the DHHS sequence, which is essential
for palmitoylation in DHHC proteins, is not required for GABPI to interact with β4GalNAcTB. In contrast, the two luminal loops
between transmembrane domain 3–4 and 5–6 contain conserved amino acids, which are crucial for activity. Besides the dependence
on GABPI, β4GalNAcTB requires its exceptional short stem region for activity. A few hydrophobic amino acids positioned close
to the transmembrane domain are essential for the interaction with GABPI. Along with its catalytic domain, β4GalNAcTB, thus,
requires an area in its own stem region and two small luminal loops of GABPI as "add-on" domains. Moreover, some inactive
GABPI mutants could be rescued by fusion with β4GalNAcTB, indicating their importance in direct GABPI-β4GalNAcTB interaction. 相似文献
15.
Suzuki Y 《Cellular and molecular life sciences : CMLS》2008,65(3):351-353
We have proposed a chemical chaperone therapy for lysosomal diseases, based on a paradoxical phenomenon that an exogenous
competitive inhibitor of low molecular weight stabilizes the target mutant molecule and restores its catalytic activity as
a molecular chaperone intracellularly. After Fabry disease experiments, we investigated a new synthetic chaperone compound
N-octyl-4-epi-β-valienamine (NOEV) in a GM1-gangliosidosis model mice. Orally administered NOEV entered the brain through the blood-brain barrier, enhanced β-galactosidase
activity, reduced the substrate storage, and clinically improved neurological deterioration. We hope that chemical chaperone
therapy will prove useful for some patients with GM1-gangliosidosis and potentially other lysosomal storage diseases with central nervous system involvement.
Received 10 October 2007; received after revision 31 October 2007; accepted 6 November 2007 相似文献
16.
Fernández MR Porté S Crosas E Barberà N Farrés J Biosca JA Parés X 《Cellular and molecular life sciences : CMLS》2007,64(11):1419-1427
ζ-crystallins constitute a family of proteins with NADPH:quinone reductase activity found initially in mammalian lenses but
now known to be present in many other organisms and tissues. Few proteins from this family have been characterized, and their
function remains unclear. In the present work, ζ-crystallins from human and yeast (Zta1p) were expressed, purified and characterized.
Both enzymes are able to reduce ortho-quinones in the presence of NADPH but are not active with 2-alkenals. Deletion of the ZTA1 gene makes yeast more sensitive to menadione and hydrogen peroxide, suggesting a role in the oxidative stress response. The
human and yeast enzymes specifically bind to adenine-uracil rich elements (ARE) in RNA, indicating that both enzymes are ARE-binding
proteins and that this property has been conserved in ζ-crystallins throughout evolution. This supports a role for ζ-crystallins
as trans-acting factors that could regulate the turnover of certain mRNAs.
Received 21 February 2007; received after revision 16 April 2007; accepted 23 April 2007
M. R. Fernández, S. Porté: These authors contributed equally to this work. 相似文献
17.
Cell adhesion molecules (CAMs) have been implicated in the control of a wide variety of cellular processes, such as cell adhesion,
polarization, survival, movement, and proliferation. Nectins have emerged as immunoglobulin-like CAMs that participate in
calcium-independent cell-cell adhesion by homophilic and heterophilic trans-interactions with nectins and nectin-like molecules. Nectin-based cell-cell adhesion exerts its function independently or
in cooperation with other CAMs including cadherins and is essential for the formation of intercellular junctions, including
adherens junctions, tight junctions, and puncta adherentia junctions. Nectins cis-interact with integrin αvβ3 and platelet-derived growth factor receptor and facilitate their signals to regulate the formation and integrity of intercellular
junctions and cell survival. Nectins intracellularly associate with peripheral membrane proteins, including afadin and Par-3.
This review focuses on recent progress in understanding the interactions of nectins with other transmembrane and peripheral
membrane proteins to exert pleiotropic functions.
Received 27 June 2007; received after revision 14 August 2007; accepted 12 September 2007 相似文献
18.
T. Shindo A. Sato H. Horikoshi H. Kuwano 《Cellular and molecular life sciences : CMLS》1992,48(7):688-690
Separation of a lipophilic extract of a soft coral,Sinularia sp., assayed by enhancement of glucose transport in rat adipocytes, gave farnesyl 4-O--D-arabinopyranosyl--D-arabinopyranoside-2,2,3-triacetate (1a) whose structure was determined by spectroscopy. Enhancers of glucose transport may be useful for the prevention and treatment of diabetic disorders. 相似文献
19.
20.
Kristin T. Jacobsen Kerstin Iverfeldt 《Cellular and molecular life sciences : CMLS》2009,66(14):2299-2318
The Alzheimer’s amyloid precursor protein (APP) belongs to a conserved gene family that also includes the mammalian APLP1
and APLP2, the Drosophila APPL, and the C. elegans APL-1. The biological function of APP is still not fully clear. However, it is known that the APP family proteins have redundant
and partly overlapping functions, which demonstrates the importance of studying all APP family members to gain a more complete
picture. When APP was first cloned, it was speculated that it could function as a receptor. This theory has been further substantiated
by studies showing that APP and its homologues bind both extracellular ligands and intracellular adaptor proteins. The APP
family proteins undergo regulated intramembrane proteolysis (RIP), generating secreted and cytoplasmic fragments that have
been ascribed different functions. In this review, we will discuss the APP family with focus on biological functions, binding
partners, and regulated processing. 相似文献