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1.
Parkinson’s disease (PD) is characterized by the death of dopaminergic neurons and the presence of Lewy bodies in the substantia
nigra pars compacta. The mechanisms involved in the death of neurons as well as the role of Lewy bodies in the pathogenesis
of the disease are still unclear. Lewy bodies are made of aggregated proteins, in which α-synuclein represents their major
component. α-Synuclein interacts with synphilin-1, a protein that is also present in Lewy bodies. When expressed in cells,
synphilin-1 forms inclusions together with α-synuclein that resemble Lewy bodies. Synphilin-1 is ubiquitylated by various
E3 ubiquitin-ligases, such as SIAH, parkin and dorfin. Ubiquitylation of synphilin-1 by SIAH is essential for its aggregation
into inclusions. We recently identified a new synphilin-1 isoform, synphilin-1A, that is toxic to neurons, aggregation-prone
and accumulates in detergent-insoluble fractions of brains from α-synucleinopathy patients. Synphilin-1A inclusions recruit
both α-synuclein and synphilin-1. Aggregation of synphilin-1 and synphilin-1A seems to be protective to cells. We now discuss
several aspects of the neurobiology and pathology of synphilin-1 isoforms, focusing on possible implications for PD.
Received 26 July 2007; received after revision 19 September 2007; accepted 15 October 2007 相似文献
2.
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
3.
Yuan J Dong Z Guo JP McGeehan J Xiao X Wang J Cali I McGeer PL Cashman NR Bessen R Surewicz WK Kneale G Petersen RB Gambetti P Zou WQ 《Cellular and molecular life sciences : CMLS》2008,65(4):631-643
Human prion diseases are characterized by the accumulation in the brain of proteinase K (PK)-resistant prion protein designated
PrP27 – 30 detectable by the 3F4 antibody against human PrP109 – 112. We recently identified a new PK-resistant PrP species,
designated PrP*20, in uninfected human and animal brains. It was preferentially detected with the 1E4 antibody against human PrP 97 – 108 but
not with the anti-PrP 3F4 antibody, although the 3F4 epitope is adjacent to the 1E4 epitope in the PrP*20 molecule. The present study reveals that removal of the N-terminal amino acids up to residue 91 significantly increases accessibility
of the 1E4 antibody to PrP of brains and cultured cells. In contrast to cells expressing wild-type PrP, cells expressing pathogenic
mutant PrP accumulate not only PrP*20 but also a small amount of 3F4-detected PK-resistant PrP27 – 30. Remarkably, during the course of human prion disease, a
transition from an increase in 1E4-detected PrP*20 to the occurrence of the 3F4-detected PrP27 – 30 was observed. Our study suggests that an increase in the level of PrP*20 characterizes the early stages of prion diseases.
Received 17 October 2007; received after revision 5 December 2007; accepted 14 December 2007 相似文献
4.
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
5.
6.
Hyaluronan synthesis and degradation in cartilage and bone 总被引:1,自引:0,他引:1
Bastow ER Byers S Golub SB Clarkin CE Pitsillides AA Fosang AJ 《Cellular and molecular life sciences : CMLS》2008,65(3):395-413
Hyaluronan (HA) is a large but simple glycosaminoglycan composed of repeating D-glucuronic acid, β1–3 linked to N-acetyl-D-glucosamine β1–4, found in body fluids and tissues, in both intra- and extracellular compartments. Despite its structural
simplicity, HA has diverse functions in skeletal biology. In development, HA-rich matrices facilitate migration and condensation
of mesenchymal cells, and HA participates in joint cavity formation and longitudinal bone growth. In adult cartilage, HA binding
to aggrecan immobilises aggrecan, retaining it at the high concentrations required for compressive resilience. HA also appears
to regulate bone remodelling by controlling osteoclast, osteoblast and osteocyte behaviour. The functions of HA depend on
its intrinsic properties, which in turn rely on the degree of polymerisation by HA synthases, depolymerisation by hyaluronidases,
and interactions with HA-binding proteins. HA synthesis and degradation are closely regulated in skeletal tissues and aberrant
synthetic or degradative activity causes disease. The role and regulation of HA synthesis and degradation in cartilage, bone
and skeletal development is discussed.
Received 5 August 2007; received after revision 19 September 2007; accepted 20 September 2007 相似文献
7.
Gemma Olmos María I. Arenas Raquel Bienes María Jose Calzada Julián Aragonés Maria Laura Garcia-Bermejo Manuel O. Landazuri Javier Lucio-Cazaña 《Cellular and molecular life sciences : CMLS》2009,66(13):2167-2180
Hypoxia-inducible factor-1α (HIF-1α) protein is degraded under normoxia by its association to von Hippel-Lindau protein (pVHL)
and further proteasomal digestion. However, human renal cells HK-2 treated with 15-deoxy-Δ12,14-prostaglandin-J2 (15d-PGJ2) accumulate HIF-1α in normoxic conditions. Thus, we aimed to investigate the mechanism involved in this accumulation. We
found that 15d-PGJ2 induced an over-accumulation of HIF-1α in RCC4 cells, which lack pVHL and in HK-2 cells treated with inhibitors of the pVHL-proteasome
pathway. These results indicated that pVHL-proteasome-independent mechanisms are involved, and therefore we aimed to ascertain
them. We have identified a new lysosomal-dependent mechanism of HIF-1α degradation as a target for 15d-PGJ2 based on: (1) HIF-1α colocalized with the specific lysosomal marker Lamp-2a, (2) 15d-PGJ2 inhibited the activity of cathepsin B, a lysosomal protease, and (3) inhibition of lysosomal activity did not result in over-accumulation
of HIF-1α in 15d-PGJ2-treated cells. Therefore, expression of HIF-1α is also modulated by lysosomal degradation. 相似文献
8.
The application of fractal dimension-based constructs to probe the protein interior dates back to the development of the concept
of fractal dimension itself. Numerous approaches have been tried and tested over a course of (almost) 30 years with the aim
of elucidating the various facets of symmetry of self-similarity prevalent in the protein interior. In the last 5 years especially,
there has been a startling upsurge of research that innovatively stretches the limits of fractal-based studies to present
an array of unexpected results on the biophysical properties of protein interior. In this article, we introduce readers to
the fundamentals of fractals, reviewing the commonality (and the lack of it) between these approaches before exploring the
patterns in the results that they produced. Clustering the approaches in major schools of protein self-similarity studies,
we describe the evolution of fractal dimension-based methodologies. The genealogy of approaches (and results) presented here
portrays a clear picture of the contemporary state of fractal-based studies in the context of the protein interior. To underline
the utility of fractal dimension-based measures further, we have performed a correlation dimension analysis on all of the
available non-redundant protein structures, both at the level of an individual protein and at the level of structural domains.
In this investigation, we were able to separately quantify the self-similar symmetries in spatial correlation patterns amongst
peptide–dipole units, charged amino acids, residues with the π-electron cloud and hydrophobic amino acids. The results revealed
that electrostatic environments in the interiors of proteins belonging to ‘α/α toroid’ (all-α class) and ‘PLP-dependent transferase-like’
domains (α/β class) are highly conducive. In contrast, the interiors of ‘zinc finger design’ (‘designed proteins’) and ‘knottins’
(‘small proteins’) were identified as folds with the least conducive electrostatic environments. The fold ‘conotoxins’ (peptides)
could be unambiguously identified as one type with the least stability. The same analyses revealed that peptide–dipoles in
the α/β class of proteins, in general, are more correlated to each other than are the peptide–dipoles in proteins belonging
to the all-α class. Highly favorable electrostatic milieu in the interiors of TIM-barrel, α/β-hydrolase structures could explain
their remarkably conserved (evolutionary) stability from a new light. Finally, we point out certain inherent limitations of
fractal constructs before attempting to identify the areas and problems where the implementation of fractal dimension-based
constructs can be of paramount help to unearth latent information on protein structural properties. 相似文献
9.
Eleonora Dondossola Anna Gasparri Angela Bachi Renato Longhi Marie-Hélène Metz-Boutigue Bruno Tota Karen B. Helle Flavio Curnis Angelo Corti 《Cellular and molecular life sciences : CMLS》2010,67(12):2107-2118
Fibroblast adhesion can be modulated by proteins released by neuroendocrine cells and neurons, such as chromogranin A (CgA)
and its N-terminal fragment vasostatin-1 (VS-1, CgA1–78). We have investigated the mechanisms of the interaction of VS-1 with fibroblasts and of its pro-adhesive activity and have
found that the proadhesive activity of VS-1 relies on its interaction with the fibroblast membrane via a phospholipid-binding
amphipathic α-helix located within residues 47–66, as well as on the interaction of the adjacent C-terminal region 67–78,
which is structurally similar to ezrin–radixin–moesin-binding phosphoprotein 50 (a membrane-cytoskeleton adapter protein),
with other cellular components critical for the regulation of cell cytoskeleton. 相似文献
10.
Heat shock protein 60: regulatory role on innate immune cells 总被引:1,自引:0,他引:1
Human heat shock protein 60 (Hsp60) exhibits immunoregulatory properties, primarily by inducing pro-inflammatory responses
in innate immune cells. Extensive analyses identified specific receptor structures for the interaction of Hsp60 with these
cells. The existence of distinct receptor structures responsible for Hsp60 binding and for Hsp60-induced release of pro-inflammatory
mediators has been demonstrated, implying that the interaction of Hsp60 with innate immune cells is a multifaceted process.
Distinct Hsp60 epitopes responsible for binding to innate immune cells and for the activation of these cells have been identified.
Depending on the cell-type, the amino acid (aa) region 481–500 or the regions aa241–260, aa391–410 and aa461–480 are involved
in Hsp60-binding to innate immune cells. An entirely different Hsp60-region, aa354–365 was found to bind lipopolysaccharide,
thereby mediating the pro-inflammatory effects of Hsp60. Because of its immunoregulatory properties, Hsp60 has been proposed
to act as intercellular danger signal, controlling innate and adaptive immune reactions.
Received 19 September 2006; received after revision 13 October 2006; accepted 13 December 2006 相似文献
11.
Ronda Bransteitter Courtney Prochnow Xiaojiang S. Chen 《Cellular and molecular life sciences : CMLS》2009,66(19):3137-3147
The apolipoprotein B mRNA-editing enzyme catalytic polypeptide (APOBEC) family of cytidine deaminases has emerged as an intensively
studied field as a result of their important biological functions. These enzymes are involved in lipid metabolism, antibody
diversification, and the inhibition of retrotransposons, retroviruses, and some DNA viruses. The APOBEC proteins function
in these roles by deaminating single-stranded (ss) DNA or RNA. There are two high-resolution crystal structures available
for the APOBEC family, Apo2 and the C-terminal catalytic domain (CD2) of Apo3G or Apo3G-CD2 [Holden et al. (Nature 456:121–124,
2008); Prochnow et al. (Nature 445:447–451, 2007)]. Additionally, the structure of Apo3G-CD2 has also been determined using
NMR [Chen et al. (Nature 452:116–119, 2008); Furukawa et al. (EMBO J 28:440–451, 2009); Harjes et al. (J Mol Biol, 2009)].
A detailed structural analysis of the APOBEC proteins and a comparison to other zinc-coordinating deaminases can facilitate
our understanding of how APOBEC proteins bind nucleic acids, recognize substrates, and form oligomers. Here, we review the
recent development of structural and functional studies that apply to Apo3G as well as the APOBEC deaminase family. 相似文献
12.
This review describes the properties of some rare eukaryotic chaperones that each assist in the folding of only one target
protein. In particular, we describe (1) the tubulin cofactors, (2) p47, which assists in the folding of collagen, (3) α-hemoglobin
stabilizing protein (AHSP), (4) the adenovirus L4-100 K protein, which is a chaperone of the major structural viral protein,
hexon, and (5) HYPK, the huntingtin-interacting protein. These various-sized proteins (102–1,190 amino acids long) are all
involved in the folding of oligomeric polypeptides but are otherwise functionally unique, as they each assist only one particular
client. This raises a question regarding the biosynthetic cost of the high-level production of such chaperones. As the clients
of faithful chaperones are all abundant proteins that are essential cellular or viral components, it is conceivable that this
necessary metabolic expenditure withstood evolutionary pressure to minimize biosynthetic costs. Nevertheless, the complexity
of the folding pathways in which these chaperones are involved results in error-prone processes. Several human disorders associated
with these chaperones are discussed. 相似文献
13.
Differential use of an in-frame translation initiation codon regulates human mu opioid receptor (OPRM1) 总被引:1,自引:1,他引:0
Kyu Young Song Hack Sun Choi Cheol Kyu Hwang Chun Sung Kim Ping-Yee Law Li-Na Wei Horace H. Loh 《Cellular and molecular life sciences : CMLS》2009,66(17):2933-2942
The pharmacological effects of morphine and morphine-like drugs are mediated primarily through the μ opioid receptor. Here
we show that differential use of an in-frame translational start codon in the 5′-untranslated region of the OPRM1 generates
different translational products in vivo and in vitro. The 5′-end of the OPRM1 gene is necessary for initiating the alternate
form and for subsequent degradation of the protein. Initiation of OPRM1 at the upstream site decreases the initiation at the
main AUG site. However, alternative initiation of the long form of OPRM1 produces a protein with a short half-life, resulting
from degradation mediated by the ubiquitin–proteasome pathway. Reporter and degradation assays showed that mutations of this
long form at the second and third lysines reduce ubiquitin-dependent proteasome degradation, stabilizing the protein. The
data suggest that MOP expression is controlled in part by initiation of the long form of MOP at the alternate site. 相似文献
14.
The public perception of selenium has changed significantly over the last decades. Originally mainly known for its high toxicity,
it was later recognized as an essential trace element and is now (despite its narrow therapeutic window) almost being marketed
as a lifestyle drug. Indeed, some clinical and preclinical studies suggest that selenium supplementation may be beneficial
in a large number of clinical conditions. However, its mode of action is unresolved in most of these cases. Selenocysteine
– identified as the 21st amino acid used in ribosome-mediated protein synthesis – is incorporated in at least 25 specific, genetically determined
human selenoproteins, many of which have only recently been discovered. Restoration of normal selenoprotein levels may be
– apart from direct supranutritional effects – one possible explanation for the effects of selenium supplements. In this review
we provide a brief but up-to-date overview of what is currently known about these 25 acknowledged human selenoproteins and
their synthesis.
Received 30 March 2005; received after revision 4 July 2005; accepted 13 July 2005 相似文献
15.
M. V. Nogués M. Moussaoui E. Boix M. Vilanova M. Ribó C. M. Cuchillo 《Cellular and molecular life sciences : CMLS》1998,54(8):766-774
The enzymatic catalysis of polymeric substrates such as proteins, polysaccharides or nucleic acids requires precise alignment
between the enzyme and the substrate regions flanking the region occupying the active site. In the case of ribonucleases,
enzyme-substrate binding may be directed by electrostatic interactions between the phosphate groups of the RNA molecule and
basic amino acid residues on the enzyme. Specific interactions between the nitrogenated bases and particular amino acids in
the active site or adjacent positions may also take place. The substrate-binding subsites of ribonuclease A have been characterized
by structural and kinetic studies. In addition to the active site (p1 ), the role of other noncatalytic phosphate-binding subsites in the correct alignment of the polymeric substrate has been
proposed. p2 and p0 have been described as phosphate-binding subsites that bind the phosphate group adjacent to the 3′ side and 5′ side, respectively,
of the phosphate in the active site. In both cases, basic amino acids (Lys-7 and Arg-10 in p2 , and Lys-66 in p0 ) are involved in binding. However, these binding sites play different roles in the catalytic process of ribonuclease A.
The electrostatic interactions in p2 are important both in catalysis and in the endonuclease activity of the enzyme, whilst the p0 electrostatic interaction contributes only to binding of the RNA. 相似文献
16.
Ahlsén M Carlsson-Skwirut C Jonsson AP Cederlund E Bergman T Bang P 《Cellular and molecular life sciences : CMLS》2007,64(14):1870-1880
Proteolytic cleavage of insulin-like growth factor (IGF) binding protein (IGFBP)-3 during pregnancy is likely to have both
IGF-dependent and -independent effects on maternal, placental and fetal growth and metabolism. A 30-kDa proteolytic IGFBP-3
fragment was isolated from third trimester pregnancy human serum and identified by N- and C-terminal amino acid sequence analysis
and mass spectrometry to correspond to residues 1–212 of the parent protein. This fragment is the dominating IGFBP-3 immunoreactive
species in pregnancy serum. The 30-kDa fragment was also detected in serum of non-pregnant women where it coexists with intact
IGFBP-3. Using biosensor technology, (1–212)IGFBP-3 was found to have 11-fold lower affinity for IGF-I compared to intact
IGFBP-3, while a 4-fold decrease in affinity was found for IGF-II. Tests with des(1–3)IGF-I suggest fast binding of IGF-I
to the N-terminal region of IGFBP-3 and similar affinity to a slow binding site in the C-terminal region.
Received 24 April 2007; received after revision 11 June 2007; accepted 13 June 2007 相似文献
17.
The ubiquitin–proteasome pathway of protein degradation is one of the major mechanisms that are involved in the maintenance
of the proper levels of cellular proteins. The regulation of proteasomal degradation thus ensures proper cell functions. The
family of proteins containing ubiquitin-like (UbL) and ubiquitin-associated (UBA) domains has been implicated in proteasomal
degradation. UbL–UBA domain containing proteins associate with substrates destined for degradation as well as with subunits
of the proteasome, thus regulating the proper turnover of proteins. 相似文献
18.
Romero-López C Díaz-González R Berzal-Herranz A 《Cellular and molecular life sciences : CMLS》2007,64(22):2994-3006
Hepatitis C virus (HCV) translation initiation depends on an internal ribosome entry site (IRES). We previously identified
an RNA molecule (HH363–10) able to bind and cleave the HCV IRES region. This paper characterizes its capacity to interfere
with IRES function. Inhibition assays showed that it blocks IRES activity both in vitro and in a human hepatoma cell line. Although nucleotides involved in binding and cleavage reside in separate regions of the
inhibitor HH363–10, further analysis demonstrated the strongest effect to be an intrinsic feature of the entire molecule;
the abolishment of either of the two activities resulted in a reduction in its function. Probing assays demonstrate that HH363–10
specifically interacts with the conserved IIIf domain of the pseudoknot structure in the IRES, leading to the inhibition of
the formation of translationally competent 80S particles. The combination of two inhibitory activities targeting different
sequences in a chimeric molecule may be a good strategy to avoid the emergence of resistant viral variants.
Received 26 July 2007; received after revision 24 September 2007; accepted 26 September 2007 相似文献
19.
As the site of gene expression and regulation, the nucleus is the control center of the cell. It might be thought that degradation
of nuclear contents is strictly ‘off-limits,’ given the importance of the genetic information contained within the nucleus,
but it has recently been reported that partial degradation of the nucleus may occur in yeast. Here we summarize the evidence
for the degradation and quality control of proteins found with the nucleus and its compartments, and of nucleic acids that
may occur under certain specific conditions. Only under certain special conditions such as differentiation of the lens are
the entire nuclear contents degraded.
Received 6 September 2006; received after revision 25 October 2006; accepted 13 December 2006 相似文献
20.
Regulation of caldesmon activity by Cdc2 kinase plays an important role in maintaining membrane cortex integrity during cell division 总被引:1,自引:0,他引:1
Li Y Wessels D Wang T Lin JL Soll DR Lin JJ 《Cellular and molecular life sciences : CMLS》2003,60(1):198-211
To study the mitosis-specific phosphorylation of caldesmon (CaD), we generated a mutant of the C-terminal fragment (amino
acids 244–538) of human fibroblast CaD (CaD39-6F), as well as a mutant of the full-length CaD (CaD-6F), in which all six potential
phosphorylation sites for Cdc2 kinase were abolished. The mitotic CaD39-6F-overexpressing cells required more time to progress
from anaphase start to 50% cytokinesis, exhibited larger size, and abnormally formed numerous small blebs. In contrast, overexpression
of the wild-type C-terminal fragment of CaD (CaD39) did not result in abnormal bleb formation, but led to larger size and
prolonged the time requirement between anaphase start and 50% cytokinesis. Similar abnormal blebs were also observed in the
CaD-6F-overexpressing cells. CaD-6F-overexpressing cells did not show larger size but required more time to progress from
anaphase start to 50% cytokinesis. These results suggest that mitosis-specific phosphorylation of CaD plays a role in inhibiting
bleb formation and that the N-terminal fragment of CaD is required for cell size determination.
Received 4 September 2002; received after revision 25 November 2002; accepted 4 December 2002 相似文献