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451.
The yeast serine threonine kinase Atg1 appears to be a key regulator of autophagy and its kinase activity is crucial for autophagy induction. Recent reports have indicated that a mammalian Atg1 homolog, UNC-51-like kinase (ULK) 1, is required for autophagy. We found that ULK1 localizes to the autophagic isolation membrane and its kinase activity is important for autophagy induction. Furthermore, we identified a focal adhesion kinase (FAK) family interacting protein of 200 kD (FIP200) as a ULK-interacting protein. FIP200 also localizes to the isolation membrane together with ULK. Using FIP200-deficient cells, we found that FIP200 is essential for autophagosome formation and the proper function of ULK. Here, we discuss the role of the ULK-FIP200 complex in autophagy and the possibility that FIP200 functions as a mammalian counterpart of Atg17. 相似文献
452.
The low density lipoprotein receptor (LDLR) plays a key role in plasma
cholesterol homeostasis by binding and internalizing lipoprotein ligands.
Studies have revealed that one or more of the seven LDL type A repeats
(LA1–LA7) in the receptor are responsible for apolipoprotein binding. In
the present study, protein engineering was performed to swap or replace key LA
repeats in a recombinant soluble LDLR (sLDLR). Although wild type sLDLR showed
strong ligand binding activity, an sLDLR variant in which LA repeat 5 was
replaced by a second copy of LA repeat 2 showed low binding activity.
Likewise, a variant wherein LA repeats 2 and 5 were swapped displayed low
binding activity. At the same time, substitution of LA repeat 2 with a second
a copy of repeat 5 resulted in a receptor with ligand binding activity similar
to wild type LDLR. When binding assays were conducted with human low density
lipoprotein as ligand, LA repeat order was a less important determinant of
binding activity. Taken together, the data indicate that the sequential order
of LA repeats plays a key role in ligand binding properties of LDLR.The low density lipoprotein receptor
(LDLR)3 plays an
important role in plasma cholesterol homeostasis
(1). A fundamental function of
LDLR is transport of cholesterol-rich lipoproteins into cells via
receptor-mediated endocytosis
(2). Human LDLR is 839 amino
acids in length and is comprised of five distinct modules that arose from gene
duplication. At the N terminus of LDLR, there exists a series of seven
imperfect, disulfide bond-rich, LDL type A (LA) repeats, each ∼40 amino
acids in length. Calcium binding induces LA repeats to fold into a ligand
binding-competent conformation
(3). Adjacent to the ligand
binding module is a ∼400-residue module that bears homology to epidermal
growth factor (EGF) precursor. This module consists of two disulfide bond-rich
EGF-like repeats (A and B) and a YWTD β-propeller motif followed by a
third EGF-like repeat C (4).
The third module of LDLR is distinguished by an abundance of O-linked
sugars, whereas the fourth module is comprised of a single membrane-spanning
sequence. Finally, a short intracellular C-terminal cytoplasmic domain,
required for receptor internalization, is present
(5).LDLR binds two apolipoprotein ligands, apolipoprotein (apo) E and apoB
(6). Although these proteins do
not share structural similarity, sequence elements rich in positively charged
amino acid side chains are present in each that are required for binding.
Deletion studies have demonstrated that specific LA repeats are required for
apolipoprotein binding to LDLR
(7,
8).Recently, another LDLR ligand, termed proprotein convertase subtilisin-like
kexin type 9 (PCSK9), has emerged
(9): PCSK9 serves to regulate
cholesterol homeostasis by modulating LDLR processing. Unlike lipoprotein
ligands, PCSK9 binds EGF repeat A and, apparently, is not released from the
receptor at endosomal pH.LA1–LA7 are ∼40–50% identical in primary sequence. Each
repeat contains a Ca2+ binding site and three disulfide bonds. The
importance of these structural features for ligand binding is widely
recognized. For example, it is known that LA5 is essential for optimal binding
of apoB- and apoE-containing ligands
(7,
8). On the other hand, deletion
of LA2 had no effect on binding of apoE-containing lipoproteins. X-ray crystal
structure information is available for isolated LA5 at pH 5.0
(10) as well as the entire
ectodomain of LDLR (residues 1–699) at endosomal pH
(11). Based on this structural
information and complementary data on apolipoprotein ligands, it has been
postulated that electrostatic interactions modulate LDLR conformation and
ligand binding. Given this, it remains unclear whether the precise order of LA
repeats within the ligand binding module may impact ligand binding.In the present study, protein engineering of a soluble LDLR (sLDLR) was
performed to swap or replace specific LA repeats within the ligand binding
module of sLDLR. Ligand binding to wild type (WT) and engineered sLDLR was
then determined. The results show that LA repeat 5 must not only be present,
it must exist in the correct context with respect to other LA repeats within
the ligand binding module. 相似文献
453.
A novel synthesis of furanodictines A [2-acetamido-3,6-anhydro-2-deoxy-5-O-isovaleryl-d-glucofuranose (1)] and B [2-acetamido-3,6-anhydro-2-deoxy-5-O-isovaleryl-d-mannofuranose (2)] is described starting from 2-acetamido-2-deoxy-d-glucose (GlcNAc). The synthetic protocol is based on deriving the epimeric bicyclic 3,6-anhydro sugars [2-acetamido-3,6-anhydro-2-deoxy-d-glucofuranose (4) and 2-acetamido-3,6-anhydro-2-deoxy-d-mannofuranose (5)] from GlcNAc. Reaction with borate upon heating led to a facile transformation of GlcNAc into the desired epimeric 3,6-anhydro sugars. The C5 hydroxyl group of the 3,6-anhydro compounds 4 and 5 was regioselectively esterified with the isovaleryl chloride to complete the synthesis of furanodictines A and B, respectively. The targets 1 and 2 were synthesized in only two steps requiring no protection/deprotection. 相似文献
454.
Ohta M Ishida A Toda M Akita K Inoue M Yamashita K Watanabe M Murata T Usui T Nakada H 《Biochemical and biophysical research communications》2010,402(4):663-669
Dendritic cells (DCs) play an essential role in the induction and maintenance of an effective immune response and express multiple siglecs. In the present study, we investigated whether or not the ligation of tumor-produced mucins with Siglec-9 expressed on immature DCs is related to escape from immunosurveillance in the tumor-bearing state.Expression of Siglec-9 was up-regulated on the development of monocytes into immature DCs and was decreased in mature DCs. Binding of various mucins and artificial glycopolymers carrying poly (NeuAc α2,6 LacNAc) or poly (NeuAc α2,3 LacNAc) to Siglec-9 was demonstrated by means of a plate assay. These mucins also bound to the surface of immature DCs. When immature DCs were treated with LPS in the presence of these mucins or artificial glycopolymers, the production of IL-12 was significantly reduced, but that of IL-10 was not. Furthermore, IL-12 production was decreased to a similar level on treatment with anti-Siglec-9 mAb. Mucins prepared from serum of cancer patients actually could bind to Siglec-9. These results suggest that Siglec-9 expressed on DCs is involved in immunoregulation through ligation with mucins in an epithelial cancer patient. 相似文献
455.
Makoto Fujii Takashi Kanematsu Hitoshi Ishibashi Kiyoko Fukami Tadaomi Takenawa Keiichi I. Nakayama Stephen J. Moss Junichi Nabekura Masato Hirata 《The Journal of biological chemistry》2010,285(7):4837-4846
The γ-aminobutyric acid type A (GABAA) receptors play a pivotal role in fast synaptic inhibition in the central nervous system. One of the key factors for determining synaptic strength is the number of receptors on the postsynaptic membrane, which is maintained by the balance between cell surface insertion and endocytosis of the receptors. In this study, we investigated whether phospholipase C-related but catalytically inactive protein (PRIP) is involved in insulin-induced GABAA receptor insertion. Insulin potentiated the GABA-induced Cl− current (IGABA) by about 30% in wild-type neurons, but not in PRIP1 and PRIP2 double-knock-out (DKO) neurons, suggesting that PRIP is involved in insulin-induced potentiation. The phosphorylation level of the GABAA receptor β-subunit was increased by about 30% in the wild-type neurons but not in the mutant neurons, which were similar to the changes observed in IGABA. We also revealed that PRIP recruited active Akt to the GABAA receptors by forming a ternary complex under insulin stimulation. The disruption of the binding between PRIP and the GABAA receptor β-subunit by PRIP interference peptide attenuated the insulin potentiation of IGABA. Taken together, these results suggest that PRIP is involved in insulin-induced GABAA receptor insertion by recruiting active Akt to the receptor complex. 相似文献
456.
Several periodic motifs have been implicated in facilitating the bending of DNA around the histone core of the nucleosome. For example, di-nucleotides AA/TT/TA and GC at ∼10-bp periods, but offset by 5 bp, are found with higher-than-expected occurrences in aligned nucleosomal DNAs in vitro and in vivo. Additionally, regularly oscillating period-10 trinucleotide motifs non-T, A/T, G and their complements have been implicated in the formation of regular nucleosome arrays. The effects of these periodic motifs on nucleosome formation have not been systematically tested directly by competitive reconstitution assays. We show that, in general, none of these period-10 motifs, except TA, in certain sequence contexts, facilitates nucleosome formation. The influence of periodic TAs on nucleosome formation is appreciable; with some of the 200-bp DNAs out-competing bulk nucleosomal DNA by more than 400-fold. Only the nucleotides immediately flanking TA influence its nucleosome-forming ability. Period-10 TA, when flanked by a pair of permissive nucleotides, facilitates DNA bending through compression of the minor groove. The free energy change for nucleosome formation decreases linearly with the number of consecutive TAs, up to eight. We suggest how these data can be reconciled with previous findings. 相似文献
457.
Isao Karube Tadashi Matsunaga Shuichi Suzuki Taichi Asano Satoshi Itoh 《Journal of biotechnology》1984,1(5-6)
A flow-type enzyme immunosensor was prepared for the electrochemical determination of human serum albumin (HSA). The immunosensor was constructed from the immobilized antibody (anti-HSA IgG) reactor and an oxygen electrode. The immunochemical reaction of catalase-labelled antibody with HSA was completed with 30 min. After the immunochemical reaction, hydrogen peroxide solution was injected into the system and a peak current was obtained within 2 min. A linear relationship was observed between the current increase and the logarithm of HSA concentration in the range 10−8-10−6 g ml−1. The minimum measurable concentration was 10−8 g ml−1. The current increase was reproducible with 10% of the relative errors when a sample solution containing 10−7 g ml−1 of HSA was used. The minimum measurable concentration increased to 10−9 g ml−1 when hydrogen peroxide was recycled for 5 min in the reactor system. The immobilized antibody reactor could be reused. HSA in human serum was determined by the system proposed. 相似文献
458.
Thyrotropin releasing hormone (TRH) caused significant breakdown of phosphatidylinositol 4,5-bisphosphate (PIP2) in GH3 cells, but vasoactive intestinal peptide (VIP) did not. However, VIP enhanced the TRH-induced hydrolysis of PIP2, the conversion of phosphatidylinositol 4-phosphate (PIP) to PIP2 and the accumulation of phosphatidic acid (PA). On the other hand, the tumor promoter, tetradecanoyl phorbol acetate (TPA), suppressed the TRH-induced hydrolysis of PIP2. In the membrane fraction, the addition of cAMP inhibited the PI kinase activity in a dose-dependent manner, but stimulated the PIP kinase activity. TPA did not affect the PI and PIP kinase activities at all. VIP enhanced the first spike phase of the TRH-induced increase in the intracellular Ca2+ level, while TPA inhibited such Ca2+ mobilization. These results suggested that cAMP-increasing agents enhanced inositol phospholipid metabolism and Ca2+ mobilization induced by TRH in GH3 cells but that TPA inhibited them. 相似文献
459.
Phosphatidylinositol 4,5-bisphosphate phosphatase regulates the rearrangement of actin filaments. 总被引:7,自引:0,他引:7
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Phosphatidylinositol 4,5-bisphosphate (PIP2) reorganizes actin filaments by modulating the functions of a variety of actin-regulatory proteins. Until now, it was thought that bound PIP2 is hydrolyzed only by tyrosine-phosphorylated phospholipase Cgamma (PLCgamma) after the activation of tyrosine kinases. Here, we show a new mechanism for the hydrolysis of bound PIP2 and the regulation of actin filaments by PIP2 phosphatase (synaptojanin). We isolated a 150-kDa protein (p150) from brains that binds the SH3 domains of Ash/Grb2. The sequence of this protein was found to be homologous to that of synaptojanin. The expression of p150 in COS 7 cells produces a decrease in the number of actin stress fibers in the center of the cells and causes the cells to become multinuclear. On the other hand, the expression of a PIP2 phosphatase-negative mutant does not disrupt actin stress fibers or produce the multinuclear phenotype. We have also shown that p150 forms the complexes with Ash/Grb2 and epidermal growth factor (EGF) receptors only when the cells are treated with EGF and that it reorganizes actin filaments in an EGF-dependent manner. Moreover, the PIP2 phosphatase activity of native p150 purified from bovine brains is not inhibited by profilin, cofilin, or alpha-actinin, although PLCdelta1 activity is markedly inhibited by these proteins. Furthermore, p150 suppresses actin gelation, which is induced by smooth muscle alpha-actinin. All these data suggest that p150 (synaptojanin) hydrolyzes PIP2 bound to actin regulatory proteins, resulting in the rearrangement of actin filaments downstream of tyrosine kinase and Ash/Grb2. 相似文献
460.
H Hayashi S Kamohara Y Nishioka F Kanai N Miyake Y Fukui F Shibasaki T Takenawa Y Ebina 《The Journal of biological chemistry》1992,267(31):22575-22580
After adding insulin to cells overexpressing the insulin receptor, the activity of phosphatidylinositol (PI) 3-kinase in the anti-phosphotyrosine immunoprecipitates was rapidly and greatly increased. This enzyme may therefore be a substrate for the insulin receptor tyrosine kinase and may be one of the mediators of insulin signal transduction. However, it is unclear whether or not activated tyrosine kinase of the insulin receptor directly phosphorylates PI 3-kinase at tyrosine residue(s) and whether insulin stimulates the specific activity of PI 3-kinase. We reported previously that the 85-kDa subunit of purified PI 3-kinase was phosphorylated at tyrosine residue(s) by the insulin receptor in vitro. To examine the tyrosine phosphorylation of PI 3-kinase and change of its activity by insulin treatment in vivo, we used a specific antibody to the 85-kDa subunit of PI 3-kinase. The activity of PI 3-kinase in immunoprecipitates with the antibody against the p85 subunit of PI 3-kinase was increased about 3-fold by insulin treatment of cells overexpressing insulin receptors. Insulin treatment also stimulated the tyrosine, serine, and threonine phosphorylation of the alpha-type 85-kDa subunit of PI 3-kinase in vivo. Phosphatase treatment of the immunoprecipitates abolished the increase in PI 3-kinase activity. The phosphorylation(s) of the kinase itself, tyrosine phosphorylation(s) of associated protein(s), or the complex formation of the phosphorylated PI 3-kinase with associated proteins may increase the activity of PI 3-kinase. 相似文献