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991.
992.
Cowan-Jacob SW 《Cellular and molecular life sciences : CMLS》2006,63(22):2608-2625
Our current understanding of the structure, mechanism of action and modes of regulation of the protein tyrosine kinase family
owes a great deal to structural biology. Structures are now available for more than 20 different tyrosine kinase domains,
many of these in multiple conformational states. They form the basis for the design of experiments to further investigate
the role of different structural elements in the normal function and regulation of the protein and in the pathogenesis of
many human diseases. Once thought to be too similar to be specifically inhibited by a small molecule, structural differences
between kinases allow the design of compounds which inhibit only an acceptable few. This review gives a general overview of
protein tyrosine kinase structural biology, including a discussion of the strengths and limitations of the investigative methods
involved.
Received 2 May 2006; received after revision 21 June 2006; accepted 9 August 2006 相似文献
993.
Vastiau IM Anthonio EA Brams M Brees C Young SG Van de Velde S Wanders RJ Mannaerts GP Baes M Van Veldhoven PP Fransen M 《Cellular and molecular life sciences : CMLS》2006,63(14):1686-1699
Pex19p exhibits a broad binding specificity for peroxisomal membrane proteins (PMPs), and is essential for the formation of
functional peroxisomal membranes. Pex19p orthologues contain a C-terminal CAAX motif common to prenylated proteins. In addition, Saccharomyces cerevisiae and Chinese hamster Pex19p are at least partially farnesylated in vivo. Whether farnesylation of Pex19p plays an essential or merely ancillary role in peroxisome biogenesis is currently not clear.
Here, we show that (i) nonfarnesylated and farnesylated human Pex19p display a similar affinity towards a select set of PMPs,
(ii) a variant of Pex19p lacking a functional farnesylation motif is able to restore peroxisome biogenesis in Pex19p-deficient
cells, and (iii) peroxisome protein import is not affected in yeast and mammalian cells defective in one of the enzymes involved
in the farnesylation pathway. Summarized, these observations indicate that the CAAX box-mediated processing steps of Pex19p are dispensable for peroxisome biogenesis in yeast and mammalian cells.
Received 10 March 2006; received after revision 28 April 2006; accepted 30 May 2006 相似文献
994.
Endomannosidase processes oligosaccharides of α1-antitrypsin and its naturally occurring genetic variants in the Golgi apparatus 总被引:3,自引:0,他引:3
Torossi T Fan JY Sauter-Etter K Roth J Ziak M 《Cellular and molecular life sciences : CMLS》2006,63(16):1923-1932
Endomannosidase provides an alternate glucose-trimming pathway in the Golgi apparatus. However, it is unknown if the action
of endomannosidase is dependent on the conformation of the substrate. We have investigated the processing by endomannosidase
of the α1-antitrypsin oligosaccharides and its disease-causing misfolded Z and Hong Kong variants. Oligosaccharides of wild-type
and misfolded α1-antitrypsin expressed in castanospermine-treated hepatocytes or glucosidase II-deficient Phar 2.7 cells were
selectively processed by endomannosidase and subsequently converted to complex type oligosaccharides as indicated by Endo
H resistance and PNGase F sensitivity. Overexpression of endomannosidase in castanospermine-treated hepatocytes resulted in
processing of all oligosaccharides of wild-type and variants of α1-antitrypsin. Thus, endomannosidase does not discriminate
the folding state of the substrate and provides a back-up mechanism for completion of N-glycosylation of endoplasmic reticulum-escaped glucosylated glycoproteins. For exported misfolded glycoproteins, this would
provide a pathway for the formation of mature oligosaccharides important for their proper trafficking and correct functioning.
Received 18 April 2006; received after revision 12 June 2006; accepted 15 June 2006 相似文献
995.
Despite the current availability of several hundreds of thousands of amino acid sequences, more than 39% of the well-defined
enzyme activities (EC numbers) are not associated with any sequence in major public databases. This wide gap separating knowledge
of biochemical function and sequence information is found in nearly all classes of enzymes. Thus, there is an urgent need
to explore the 1525 orphan enzymes (EC numbers without associated sequences), in order to progressively bridge this unwanted
gap. Improving genome annotation could unveil a significant proportion of sequenceless enzymes. Peptide mass mapping and further
genome mining would be useful to identify proper sequence for enzymes found in species for which genetic tools are missing.
Finally, the whole community must help major public databases to begin addressing the problem of missing or incomplete information.
Received 31 October 2005; received after revision 8 December 2005; accepted 20 December 2005 相似文献
996.
Sarramegn V Muller I Milon A Talmont F 《Cellular and molecular life sciences : CMLS》2006,63(10):1149-1164
G protein-coupled receptors (GPCRS) represent a class of integral membrane proteins involved in many biological processes
and pathologies. Fifty percent of all modern drugs and almost 25% of the top 200 bestselling drugs are estimated to target
GPCRs. Despite these crucial biological implications, very little is known, at atomic resolution, about the detailed molecular
mechanisms by which these membrane proteins are able to recognize their extra-cellular stimuli and transmit the associated
messages. Obviously, our understanding of GPCR functioning would be greatly facilitated by the availability of high-resolution
three-dimensional (3D) structural data. However, expression, solubilization and purification of these membrane proteins are
not easy to achieve, and at present, only one 3D structure has been determined, that of bovine rhodopsin. This review presents
and compares the different successful strategies which have been applied to solubilize and purify recombinant GPCRs in the
perspective of structural biology experiments.
Received 21 November 2005; received after revision 20 January 2006; accepted 2 February 2006
An erratum to this article is available at . 相似文献
997.
Laitinen OH Hytönen VP Nordlund HR Kulomaa MS 《Cellular and molecular life sciences : CMLS》2006,63(24):2992-3017
Chicken avidin and bacterial streptavidin, (strept)avidin, are proteins widely utilized in a number of applications in life
science, ranging from purification and labeling techniques to diagnostics, and from targeted drug delivery to nanotechnology.
(Strept)avidin-biotin technology relies on the extremely tight and specific affinity between (strept)avidin and biotin (dissociation
constant, Kd≈10−14–10−16 M). (Strept)avidins are also exceptionally stable proteins. To study their ligand binding and stability characteristics,
the two proteins have been extensively modified both chemically and genetically. There are excellent accounts of this technology
and chemically modified (strept)avidins, but no comprehensive reviews exist concerning genetically engineered (strept)avidins.
To fill this gap, we here go through the genetically engineered (strept)avidins, summarizing how these constructs were designed
and how they have improved our understanding of the structural and functional characteristics of these proteins, and the benefits
they have provided for (strept)avidin-biotin technology.
Received 22 June 2006; received after revision 1 August 2006; accepted 21 September 2006 相似文献
998.
Immunophilins: for the love of proteins 总被引:1,自引:0,他引:1
Barik S 《Cellular and molecular life sciences : CMLS》2006,63(24):2889-2900
Immunophilins are chaperones that may also exhibit peptidylprolyl isomerase (PPIase) activity. This review summarizes our
knowledge of the two largest families of immunophilins, namely cyclophilin and FK506-binding protein, and a novel chimeric
dual-family immunophilin, named FK506- and cyclosporin-binding protein (FCBP). The larger members of each family are modular
in nature, consisting of multiple PPIase and/or protein-protein interaction domains. Despite the apparent difference in their
sequence and three-dimensional structure, the three families encode similar enzymatic and biological functions. Recent studies
have revealed that many immunophilins possess a chaperone function independent of PPIase activity. Knockout animal studies
have confirmed multiple essential roles of immunophilins in physiology and development. An immunophilin is indeed a natural
‘protein-philin’ (Greek ‘philin’ = friend) that interacts with proteins to guide their proper folding and assembly.
Received: 7 May 2006; received after revision 3 July 2006; accepted 24 August 2006 相似文献
999.
Facilitating the entry of molecules into mammalian cells is of great interest to fields as diverse as cell biology and drug
delivery. The discovery of natural protein transduction domains and the development of artificial ones, including polyarginine,
provides a means to achieve this goal. Here, we comment on key chemical and biological aspects of cationic peptide internalization,
including the physiological relevance of this process.
Received 13 April 2006; received after revision 21 May 2006; accepted 2 June 2006 相似文献
1000.
Olfactory ensheathing cells have been used in several studies to promote repair in the injured spinal cord. However, cellular
interaction between olfactory ensheathing cells and glial cells induced to be reactive in the aftermath of injury site has
not been investigated. Using an in vitro model of astrogliosis, we show that reactive astrocytes expressed significantly less glial fibrillary acidic protein (GFAP)
when cultured both in direct contact with olfactory ensheathing cells and when the two cell types were separated by a porous
membrane. Immunofluorescence staining also suggested that reactive astrocytes showed decreased chondroitin sulfate proteoglycans
in the presence of olfactory ensheathing cells, although the reduction was not statistically significant. No down-regulation
of GFAP was observed when reactive astrocytes were similarly cultured with Schwann cells. Cell viability assay and bromodeoxyuridine
uptake showed that proliferation of reactive astrocytes was significantly increased in the presence of olfactory ensheathing
cells and Schwann cells.
Received 27 February 2007; received after revision 30 March 2007; accepted 3 April 2007 相似文献