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排序方式: 共有103条查询结果,搜索用时 16 毫秒
41.
Arthur Laganowsky Justin L. P. Benesch Meytal Landau Linlin Ding Michael R. Sawaya Duilio Cascio Qingling Huang Carol V. Robinson Joseph Horwitz David Eisenberg 《Protein science : a publication of the Protein Society》2010,19(5):1031-1043
Small heat shock proteins alphaA and alphaB crystallin form highly polydisperse oligomers that frustrate protein aggregation, crystallization, and amyloid formation. Here, we present the crystal structures of truncated forms of bovine alphaA crystallin (AAC59–163) and human alphaB crystallin (ABC68–162), both containing the C‐terminal extension that functions in chaperone action and oligomeric assembly. In both structures, the C‐terminal extensions swap into neighboring molecules, creating runaway domain swaps. This interface, termed DS, enables crystallin polydispersity because the C‐terminal extension is palindromic and thereby allows the formation of equivalent residue interactions in both directions. That is, we observe that the extension binds in opposite directions at the DS interfaces of AAC59–163 and ABC68–162. A second dimeric interface, termed AP, also enables polydispersity by forming an antiparallel beta sheet with three distinct registration shifts. These two polymorphic interfaces enforce polydispersity of alpha crystallin. This evolved polydispersity suggests molecular mechanisms for chaperone action and for prevention of crystallization, both necessary for transparency of eye lenses. 相似文献
42.
A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis 总被引:13,自引:0,他引:13
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Nishimura AL Mitne-Neto M Silva HC Richieri-Costa A Middleton S Cascio D Kok F Oliveira JR Gillingwater T Webb J Skehel P Zatz M 《American journal of human genetics》2004,75(5):822-831
Motor neuron diseases (MNDs) are a group of neurodegenerative disorders with involvement of upper and/or lower motor neurons, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), progressive bulbar palsy, and primary lateral sclerosis. Recently, we have mapped a new locus for an atypical form of ALS/MND (atypical amyotrophic lateral sclerosis [ALS8]) at 20q13.3 in a large white Brazilian family. Here, we report the finding of a novel missense mutation in the vesicle-associated membrane protein/synaptobrevin-associated membrane protein B (VAPB) gene in patients from this family. Subsequently, the same mutation was identified in patients from six additional kindreds but with different clinical courses, such as ALS8, late-onset SMA, and typical severe ALS with rapid progression. Although it was not possible to link all these families, haplotype analysis suggests a founder effect. Members of the vesicle-associated proteins are intracellular membrane proteins that can associate with microtubules and that have been shown to have a function in membrane transport. These data suggest that clinically variable MNDs may be caused by a dysfunction in intracellular membrane trafficking. 相似文献
43.
Johnson E Cascio D Sawaya MR Gingery M Schröder I 《Structure (London, England : 1993)》2005,13(4):637-648
Ferritins are known as important iron storage/detoxification proteins and are widely found in living organisms. This report details the 2.1 A resolution native and 2.7 A resolution iron bound structures of the ferritin from the hyperthermophilic Archaeon Archaeoglobus fulgidus, and represents the first structure of a ferritin from an archaeon, or a hyperthermophilic organism. The A. fulgidus ferritin (AfFtn) monomer has a high degree of structural similarity with archetypal ferritins from E. coli and humans, but the AfFtn quaternary structure is novel; 24 subunits assemble into a shell having tetrahedral (2-3) rather than the canonical octahedral (4-3-2) symmetry of archetypal ferritins. The difference in assembly opens four large (approximately 45 A) pores in the AfFtn shell. Two nonconservative amino acid substitutions may be critical for stabilizing the tetrahedral form. 相似文献
44.
Duilio Michele Potenza Germano Guerra Daniele Avanzato Valentina Poletto Sumedha Pareek Daniele Guido Angelo Gallanti Vittorio Rosti Luca Munaron Franco Tanzi Francesco Moccia 《Cell calcium》2014
Hydrogen sulphide (H2S) is a newly discovered gasotransmitter that regulates multiple steps in VEGF-induced angiogenesis. An increase in intracellular Ca2+ concentration ([Ca2+]i) is central to endothelial proliferation and may be triggered by both VEGF and H2S. Albeit VEGFR-2 might serve as H2S receptor, the mechanistic relationship between VEGF- and H2S-induced Ca2+ signals in endothelial cells is unclear. The present study aimed at assessing whether and how NaHS, a widely employed H2S donor, stimulates pro-angiogenic Ca2+ signals in Ea.hy926 cells, a suitable surrogate for mature endothelial cells, and human endothelial progenitor cells (EPCs). We found that NaHS induced a dose-dependent increase in [Ca2+]i in Ea.hy926 cells. NaHS-induced Ca2+ signals in Ea.hy926 cells did not require extracellular Ca2+ entry, while they were inhibited upon pharmacological blockade of the phospholipase C/inositol-1,4,5-trisphosphate (InsP3) signalling pathway. Moreover, the Ca2+ response to NaHS was prevented by genistein, but not by SU5416, which selectively inhibits VEGFR-2. However, VEGF-induced Ca2+ signals were suppressed by dl-propargylglycine (PAG), which blocks the H2S-producing enzyme, cystathionine γ-lyase. Consistent with these data, VEGF-induced proliferation and migration were inhibited by PAG in Ea.hy926 cells, albeit NaHS alone did not influence these processes. Conversely, NaHS elevated [Ca2+]i only in a modest fraction of circulating EPCs, whereas neither VEGF-induced Ca2+ oscillations nor VEGF-dependent proliferation were affected by PAG. Therefore, H2S-evoked elevation in [Ca2+]i is essential to trigger the pro-angiogenic Ca2+ response to VEGF in mature endothelial cells, but not in their immature progenitors. 相似文献
45.
Mahavir Singh Fernando A. Gonzales Duilio Cascio Nathanael Heckmann Guillaume Chanfreau Juli Feigon 《The Journal of biological chemistry》2009,284(3):1906-1916
H/ACA ribonucleoprotein particles are essential for ribosomal RNA and
telomerase RNA processing and metabolism. Shq1p has been identified as an
essential eukaryotic H/ACA small nucleolar (sno) ribonucleoparticle (snoRNP)
biogenesis and assembly factor. Shq1p is postulated to be involved in the
early biogenesis steps of H/ACA snoRNP complexes, and Shq1p depletion leads to
a specific decrease in H/ACA small nucleolar RNA levels and to defects in
ribosomal RNA processing. Shq1p contains two predicted domains as follows: an
N-terminal CS (named after CHORD-containing proteins and
SGT1) or HSP20-like domain, and a C-terminal region of high
sequence homology called the Shq1 domain. Here we report the crystal structure
and functional studies of the Saccharomyces cerevisiae Shq1p CS
domain. The structure consists of a compact anti-parallel β-sandwich fold
that is composed of two β-sheets containing four and three
β-strands, respectively, and a short α-helix. Deletion studies
showed that the CS domain is required for the essential functions of Shq1p.
Point mutations in residues Phe-6, Gln-10, and Lys-80 destabilize Shq1p in
vivo and induce a temperature-sensitive phenotype with depletion of H/ACA
small nucleolar RNAs and defects in rRNA processing. Although CS domains are
frequently found in co-chaperones of the Hsp90 molecular chaperone, no
interaction was detected between the Shq1p CS domain and yeast Hsp90 in
vitro. These results show that the CS domain is essential for Shq1p
function in H/ACA snoRNP biogenesis in vivo, possibly in an
Hsp90-independent manner.Modification of uridine to pseudouridine in ribosomal RNA and some
spliceosomal RNAs is catalyzed by highly specialized ribonucleoparticle
(RNP)3 complexes
called box H/ACA RNPs
(1-5).
Depending on their site of maturation and action H/ACA RNPs are classified
into two classes, small nucleolar RNPs (snoRNPs) and small Cajal body RNPs. In
Saccharomyces cerevisiae, H/ACA snoRNPs contain four proteins: Nhp2p
(L7ae in archaea (6) and Cbf5p,
also called dyskerin, in humans
(7)), Nop10p, Gar1p, and a
single small nucleolar RNA (snoRNA), specific to each snoRNP
(8-11).
Cbf5p provides the pseudouridylase activity to the complex, and the snoRNA
component provides the “guide RNA” for positioning the substrate
RNA for modification (8,
10,
12-15).
The 3′ end of human telomerase RNA (hTR) contains an H/ACA scaRNA domain
that binds the H/ACA proteins and is required for 3′ end processing,
accumulation, and localization of hTR to Cajal bodies
(16-19).
In archaea, the assembly of H/ACA snoRNP appears to proceed by assembly of the
protein components, followed by the incorporation of the H/ACA RNA
(8,
20-23).
In eukaryotes, the assembly and final maturation of the holoenzyme RNP are
more complicated, possibly because of subcellular compartmentalization, and
require accessory proteins
(22,
24). Two proteins specifically
found in eukaryotes, Naf1p and Shq1p, were initially identified in yeast as
factors involved in the assembly of H/ACA snoRNPs
(23-25).
Both Shq1p and Naf1p are essential proteins, and their depletion leads to the
loss of H/ACA snoRNAs (22,
24). Shq1p and Naf1p interact
with the H/ACA RNP components Cbf5p and Nhp2p as shown by high throughput
proteomic approaches and by directed protein interaction studies
(24,
26-28).
Both Naf1p and Gar1p contain a central domain that forms a six-stranded
β-barrel fold and interact competitively with Cbf5p using this
“core-Gar1” domain
(29).Although Shq1p was first identified in yeast
(24), orthologues have been
found in all eukaryotic genomes investigated, including human
(22). Shq1p is not associated
with the precursor or mature RNPs and is localized in the nucleoplasm
(24) rather than in the
nucleolus or Cajal bodies where mature H/ACA RNPs reside. It was therefore
proposed that Shq1p is involved in the early biogenesis steps of H/ACA
snoRNPs. However, Shq1p does not share any homology with either Naf1p or
Gar1p, and its mode of action remains unclear. Based on the Saccharomyces
Genome Data base annotations and domain predictions, Shq1p seems to be a
modular protein with two predicted domains in its sequence
(Fig. 1A). The
C-terminal half contains a region of high sequence homology with other Shq1
proteins called the Shq1 domain, but this region shows no identified folding
motif. The N-terminal region of the protein has a predicted CS (named after
CHORD-containing proteins and SGT1) or HSP20-like
domain, which is found in a number of co-chaperones for heat shock protein 90
(Hsp90)
(30-34),
and hence is presumed to be an Hsp90 (Hsp82p in yeast) binding domain. The CS,
HSP20-like, and p23-like domains belong to the HSP20 domain superfamily.Open in a separate windowFIGURE 1.Deletion analysis and stability of Shq1p truncated mutants.
A, domain organization of Shq1p and complementation of the
shq1Δ strain by the various truncation mutants.
Numbers refer to SHQ1 amino acid residues. Cells were grown
in plates containing 5-fluoroacetic acid to counterselect the wild-type
(wt) SHQ1 copy borne by the URA3-containing plasmid
and in the absence of methionine to express Shq1p, and cell growth was
assessed. B, example of growth assay used to generate the previous
figure. Shown is the growth of strains expressing the indicated deletions of
Shq1p on a plate containing 5-fluoroacetic acid to counterselect the wild-type
SHQ1 copy borne by the URA3-containing plasmid. C,
stability of truncated mutants. Cells containing the endogenous SHQ1 copy and
the indicated constructs were grown on liquid medium in the absence of
methionine. Proteins were expressed under the control of the Met25 promoter,
which is highly induced in the absence of Met. Numbers refer to SHQ1
amino acid residues. Shq1p proteins were detected by immunoblotting with
anti-GFP. Hexokinase (Hxk) was used as a loading control.We have determined the x-ray crystal structure of the CS domain of Shq1p
and investigated its importance for Shq1p function. The structure consists of
a β-sandwich immunoglobulin light chain fold
(35). Like other CS domains,
the CS domain of Shq1p is primarily composed of two β-sheets
(30,
31,
33,
36), but it has an additional
short helix at the C terminus. We show that the Shq1p CS domain is essential
for growth in S. cerevisiae and that the integrity of the CS domain
is required for the function of Shq1p in vivo. Based on the structure
and sequence conservation among Shq1 proteins, we investigated the effect of
three single point mutations, F6A, Q10A, and K80A, on Shq1p structure and
function. All three mutations destabilized the tertiary structure of the CS
domain, albeit to differing extents. Incorporation of these mutations in Shq1p
resulted in a temperature-sensitive growth phenotype, specific depletion of
H/ACA snoRNAs, and rRNA processing defects. NMR chemical shift mapping showed
no interaction between the Shq1p CS domain and Hsp82p, suggesting that the
Shq1p CS domain does not have a canonical role as an Hsp82p co-chaperone
protein. 相似文献
46.
Santiago M Di Pietro Duilio Cascio Daniel Feliciano James U Bowie Gregory S Payne 《The EMBO journal》2010,29(6):1033-1044
During clathrin‐mediated endocytosis, adaptor proteins play central roles in coordinating the assembly of clathrin coats and cargo selection. Here we characterize the binding of the yeast endocytic adaptor Sla1p to clathrin through a variant clathrin‐binding motif that is negatively regulated by the Sla1p SHD2 domain. The crystal structure of SHD2 identifies the domain as a sterile α‐motif (SAM) domain and shows a propensity to oligomerize. By co‐immunoprecipitation, Sla1p binds to clathrin and self‐associates in vivo. Mutations in the clathrin‐binding motif that abolish clathrin binding and structure‐based mutations in SHD2 that impede self‐association result in endocytosis defects and altered dynamics of Sla1p assembly at the sites of endocytosis. These results define a novel mechanism for negative regulation of clathrin binding by an adaptor and suggest a role for SAM domains in clathrin‐mediated endocytosis. 相似文献
47.
Nicole M. Wheatley Duilio Cascio Todd O. Yeates 《Protein science : a publication of the Protein Society》2013,22(5):660-665
Bacterial microcompartments (MCPs) are large proteinaceous structures comprised of a roughly icosahedral shell and a series of encapsulated enzymes. MCPs carrying out three different metabolic functions have been characterized in some detail, while gene expression and bioinformatics studies have implicated other types, including one believed to perform g lycyl r adical‐based metabolism of 1,2‐p ropanediol (Grp). Here we report the crystal structure of a protein (GrpN), which is presumed to be part of the shell of a Grp‐type MCP in Rhodospirillum rubrum F11. GrpN is homologous to a family of proteins (EutN/PduN/CcmL/CsoS4) whose members have been implicated in forming the vertices of MCP shells. Consistent with that notion, the crystal structure of GrpN revealed a pentameric assembly. That observation revived an outstanding question about the oligomeric state of this protein family: pentameric forms (for CcmL and CsoS4A) and a hexameric form (for EutN) had both been observed in previous crystal structures. To clarify these confounding observations, we revisited the case of EutN. We developed a molecular biology‐based method for accurately determining the number of subunits in homo‐oligomeric proteins, and found unequivocally that EutN is a pentamer in solution. Based on these convergent findings, we propose the name bacterial microcompartment vertex for this special family of MCP shell proteins. 相似文献
48.
Balendiran GK Sawaya MR Schwarz FP Ponniah G Cuckovich R Verma M Cascio D 《The Journal of biological chemistry》2011,286(8):6336-6344
Diabetic tissues are enriched in an "activated" form of human aldose reductase (hAR), a NADPH-dependent oxidoreductase involved in sugar metabolism. Activated hAR has reduced sensitivity to potential anti-diabetes drugs. The C298S mutant of hAR reproduces many characteristics of activated hAR, although it differs from wild-type hAR only by the replacement of a single sulfur atom with oxygen. Isothermal titration calorimetry measurements revealed that the binding constant of NADPH to the C298S mutant is decreased by a factor of two, whereas that of NADP(+) remains the same. Similarly, the heat capacity change for the binding of NADPH to the C298S mutant is twice increased; however, there is almost no difference in the heat capacity change for binding of the NADP(+) to the C298S. X-ray crystal structures of wild-type and C298S hAR reveal that the side chain of residue 298 forms a gate to the nicotinamide pocket and is more flexible for cysteine compared with serine. Unlike Cys-298, Ser-298 forms a hydrogen bond with Tyr-209 across the nicotinamide ring, which inhibits movements of the nicotinamide. We hypothesize that the increased polarity of the oxidized nicotinamide weakens the hydrogen bond potentially formed by Ser-298, thus, accounting for the relatively smaller effect of the mutation on NADP(+) binding. The effects of the mutant on catalytic rate constants and binding constants for various substrates are the same as for activated hAR. It is, thus, further substantiated that activated hAR arises from oxidative modification of Cys-298, a residue near the nicotinamide binding pocket. 相似文献
49.
Mark A. Arbing Sum Chan Liam Harris Emmeline Kuo Tina T. Zhou Christine J. Ahn Lin Nguyen Qixin He Jamie Lu Phuong T. Menchavez Annie Shin Thomas Holton Michael R. Sawaya Duilio Cascio David Eisenberg 《PloS one》2013,8(11)
The expression of heteroligomeric protein complexes for structural studies often requires a special coexpression strategy. The reason is that the solubility and proper folding of each subunit of the complex requires physical association with other subunits of the complex. The genomes of pathogenic mycobacteria encode many small protein complexes, implicated in bacterial fitness and pathogenicity, whose characterization may be further complicated by insolubility upon expression in Escherichia coli, the most common heterologous protein expression host. As protein fusions have been shown to dramatically affect the solubility of the proteins to which they are fused, we evaluated the ability of maltose binding protein fusions to produce mycobacterial Esx protein complexes. A single plasmid expression strategy using an N-terminal maltose binding protein fusion to the CFP-10 homolog proved effective in producing soluble Esx protein complexes, as determined by a small-scale expression and affinity purification screen, and coupled with intracellular proteolytic cleavage of the maltose binding protein moiety produced protein complexes of sufficient purity for structural studies. In comparison, the expression of complexes with hexahistidine affinity tags alone on the CFP-10 subunits failed to express in amounts sufficient for biochemical characterization. Using this strategy, six mycobacterial Esx complexes were expressed, purified to homogeneity, and subjected to crystallization screening and the crystal structures of the Mycobacterium abscessus EsxEF, M. smegmatis EsxGH, and M. tuberculosis EsxOP complexes were determined. Maltose binding protein fusions are thus an effective method for production of Esx complexes and this strategy may be applicable for production of other protein complexes. 相似文献