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1.
Recently, a novel transmembrane protein was found to be up-regulated in the auditory learning pathway of birds and mammals. The protein, FnTm2, was predicted to have an extracellular fibronectin III (Fn3) domain and a single transmembrane domain. By contrast to other studied Fn3 domains the extracellular domain of FnTm2 bears several cysteine residues, which are predicted to form disulfide bonds. The Fn3 domain of the FnTm2 protein was expressed in DH5-α Escherichia coli (E. coli) cells, purified and characterized by circular dichroism (CD). In order to identify binding partners to Fn3, the isolated protein was incubated with bird brain lysate for a pull down treatment. Of the proteins recognized, myelin basic protein (MBP) was identified as a bona fide partner; it was further characterized for binding to Fn3 in vitro via fluorescence spectroscopy and confirmed via isothermal calorimetry (ITC). 相似文献
2.
H Shenoi J Seavitt A Zheleznyak M L Thomas E J Brown 《Journal of immunology (Baltimore, Md. : 1950)》1999,162(12):7120-7127
The transmembrane protein tyrosine phosphatase CD45 is required for Ag receptor signal transduction in lymphocytes. Recently, a role for CD45 in the regulation of macrophage adhesion has been demonstrated as well. To investigate further the role of CD45 in the regulation of adhesion, we examined integrin-mediated adhesion to fibronectin of two T cell lines and their CD45-deficient variants. The absence of CD45 correlated with enhanced adhesion to fibronectin via integrin alpha5beta1 (VLA-5), but not alpha4beta1 (VLA-4) in both cell lines. Adhesion returned to normal levels upon transfection of wild-type CD45 into the CD45-deficient lines. Transfection of chimeric or mutant molecules expressing some, but not all, CD45 domains and activities demonstrated that both the transmembrane domain and the tyrosine phosphatase activity of CD45 were required for regulation of integrin-dependent adhesion, but the highly glycosylated extracellular domain was dispensable. In contrast, only a catalytically active CD45 cytoplasmic domain was required for TCR signaling. Transfectants that restored normal levels of adhesion to fibronectin coimmunoprecipitated with the transmembrane protein known as CD45-associated protein. These studies demonstrate a novel role for CD45 in adhesion regulation and suggest a possible function for its association with CD45-associated protein. 相似文献
3.
A Ciarrocchi M S Rieber M Rieber 《Biochemical and biophysical research communications》1992,183(2):544-552
Cell/fibronectin adhesion in extracellular matrices is partly mediated by integrin receptor recognition of RGD domains in fibronectin. Since blood contains significant levels of soluble fibronectin we have now investigated the occurrence of extracellular RGD-binding proteins. Attachment assays indicate that extracellular RGD-binding proteins prevent cell adhesion, suggesting their potential as novel secreted modulators of blood-borne cell adhesive interactions. These extracellular RGD-binding proteins also showed electrophoretic changes with reducing agents, suggestive of intrachain disulphide bonds, like those found in RGD-binding integrins. However, they differed from the latter in their electrophoretic profile, which was greatly dependent on the presence of protease inhibitors. Plasma from tumor-bearing mice showed a greater proportion of fast-migrating RGD-binding species under reducing condition compared to similarly treated normal plasma, suggesting that tumor development is associated with a partial degradation of extracellular RGD-binding proteins. 相似文献
4.
Garwood J Theocharidis U Calco V Dobbertin A Faissner A 《Cellular and molecular neurobiology》2012,32(2):279-287
Tenascin-C (TN-C) is a multimodular glycoprotein of the extracellular matrix which is important for the development of the
nervous system and has a range of different functions which are mediated by the different protein domains present. TN-C contains
eight constitutive fibronectin type III (FNIII) domains and a region of alternatively spliced FNIII domains. In the mouse
and chick, six of these domains have been described and characterized, whereas in human there are nine of them. In this report,
we show that seven alternatively spliced FNIII domains exist in rat and describe the differential expression pattern of the
additional domain AD1 during embryonic and postnatal rat brain development. The AD1 domain of rat is homologous to the ones
described in human and chick proteins but does not exist in mouse. Its expression can be located to the developing rat hippocampus
and the lining of the lateral ventricle, regions where the TN-C protein may affect the behavior of stem and progenitor cells.
During hippocampal development AD1 and the other alternatively spliced domains are differentially expressed as shown by RT-PCRs,
immunocytochemistry and in situ hybridizations. 相似文献
5.
The leukocyte common antigen (CD45) is a transmembrane protein tyrosine phosphatase expressed only in nucleated hematopoietic cells. It can be expressed as different isoforms depending on the cell type and the state of activation or differentiation and it is known to play a crucial role in the maturation and differentiation of B and T lymphocytes. However, the regulation of CD45 expression and function has been difficult to study due to the complexity of the gene in mammals. In this paper, we report the isolation and characterization of a CD45 orthologue gene from the Japanese pufferfish Fugu rubripes (Fugu). The Fugu CD45 cDNA sequence contains an open reading frame of 1,246 amino acids with a variable extracellular region as a result of the alternative splicing of two exons. The intracellular region is organized into two highly conserved tyrosine phosphatase domains. The extracellular region is not conserved except in some structural domains. The Fugu CD45 gene has a similar exon/intron organization to that of mammals except in the 5' end where some exons are missing or fused together. By contrast, the gene is ten times smaller in Fugu due to the small size of the introns. These studies show a greater flexibility to evolve at the 5' end of the gene and provide clues to the functionally important domains of the molecule. In addition, the lower complexity of this gene in Fugu should allow easier mapping of its regulatory sequences. 相似文献
6.
MPTP delta, a putative murine homolog of HPTP delta, is expressed in specialized regions of the brain and in the B-cell lineage. 总被引:5,自引:0,他引:5
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K Mizuno K Hasegawa T Katagiri M Ogimoto T Ichikawa H Yakura 《Molecular and cellular biology》1993,13(9):5513-5523
Protein tyrosine phosphatases (PTPs), together with protein tyrosine kinases (PTKs), are involved in the regulation of cell activation, growth, and differentiation. To further elucidate the fine tuning of cell growth and differentiation through tyrosine phosphorylation, we tried to isolate mouse receptor-type PTP (RPTP) cDNA clones by screening mouse brain cDNA libraries with mouse CD45 PTP domain probes under reduced-stringency conditions. Characterization of isolated cDNA clones for RPTP showed that the cytoplasmic region contains two tandem repeats of PTP domain of about 230 amino acids with intrinsic phosphatase activity. The extracellular region was composed of immunoglobulin (Ig)-like domains and fibronectin type III (FN-III)-like domains. The gene was highly homologous to human PTP delta (HPTP delta) and thus was named MPTP delta (murine counterpart of HPTP delta). The MPTP delta gene appeared to generate at least three species of mRNA, which differ in the composition of the extracellular domain: type A, one Ig-like and four FN-III-like domains; type B, one Ig-like and eight FN-III-like domains; and type C, three Ig-like and eight FN-III-like domains. Interestingly, the 5' untranslated region and the leader peptide of types A and B were completely different from those of type C. Northern (RNA) blot analysis demonstrated that brain, kidney, and heart cells express three mRNA species of about 7 kb. Antibody directed against part of the extracellular domain of type A MPTP delta recognized a 210-kDa protein in brain and kidney lysates. In situ hybridization of brain samples revealed that MPTP delta mRNA is present in the hippocampus, thalamic reticular nucleus, and piriform cortex, where some Src family PTKs have been also demonstrated to exist. Although MPTP delta mRNA was not detected in lymphoid tissues, all of the pre-B-cell lines tested and one of three B-cell lines tested expressed MPTP delta mRNA, whereas antibody-producing B-cell hybridomas and T-cell and macrophage lines did not. Finally, the MPTP delta locus was tightly linked to the brown (b) locus on mouse chromosome 4. 相似文献
7.
8.
The MRC OX-45 antigen of rat leukocytes and endothelium is in a subset of the immunoglobulin superfamily with CD2, LFA-3 and carcinoembryonic antigens. 总被引:12,自引:1,他引:11
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The MRC OX-45 cell surface antigen is a glycoprotein of 45,000 apparent mol. wt of rat leukocytes and endothelium. Antibodies against the antigen inhibit T lymphocyte responses by stimulation of suppression by accessory cells. We now report the immunochemical characterization of this antigen and its cDNA sequence. The predicted protein sequence contains 240 amino acids including a leader sequence of 22 residues and a carboxy-terminal sequence of 23 residues that is replaced in the processed molecule by a glycosyl-phosphatidylinositol anchor attached at serine 195. Two Ig-related domains are predicted to account for all of the processed sequence and the circular dichroism spectrum shows pure beta-structure. The amino-terminal domain is V-like, but without a disulphide bond, while the second domain is C-like (C2-SET) with two disulphide bonds. The sequence matches particularly well with the extracellular parts of LFA-3 and CD2 antigens and the first two domains of carcinoembryonic antigen and non-specific, cross-reacting antigen. 相似文献
9.
10.
Three receptor-linked protein-tyrosine phosphatases are selectively expressed on central nervous system axons in the Drosophila embryo. 总被引:8,自引:0,他引:8
We describe the isolation of seven different protein-tyrosine phosphatase (PTPase) cDNAs from Drosophila embryos, three of which are primarily expressed in the central nervous system (CNS). The CNS-specific PTPases include the previously sequenced DLAR, as well as two novel PTPases (denoted DPTP10D and DPTP99A), which have extracellular domains consisting of multiple fibronectin type III repeats. Each of the Drosophila sequences is most closely related to a different human PTPase. The three PTPase mRNAs are expressed in different patterns of cells in the ventral nerve cord, and all three proteins are restricted to axons. DLAR and DPTP99A are apparently expressed on most or all axons, while DPTP10D is primarily localized to the anterior commissure and its junctions with the longitudinal tracts. 相似文献
11.
Co-operative binding of human fibronectin to Sfbl protein triggers streptococcal invasion into respiratory epithelial cells 总被引:5,自引:2,他引:3
Talay SR Zock A Rohde M Molinari G Oggioni M Pozzi G Guzman CA Chhatwal GS 《Cellular microbiology》2000,2(6):521-535
Streptococcal fibronectin binding protein I (SfbI) mediates adherence to and invasion of Streptococcus pyogenes into human epithelial cells. In this study, we analysed the binding activity of distinct domains of SfbI protein towards its ligand, the extracellular matrix component fibronectin, as well as the biological implication of the binding events during the infection process. By using purified recombinant SfbI derivatives as well as in vivo expressed SfbI domains on the surface of heterologous organism Streptococcus gordonii , we were able to dissociate the two major streptococcal target domains on the human fibronectin molecule. The SfbI repeat region exclusively bound to the 30 kDa N-terminal fragment of fibronectin, whereas the SfbI spacer region exclusively bound to the 45 kDa collagen-binding fragment of fibronectin. In the case of native surface-expressed SfbI protein, an induced fit mode of bacteria–fibronectin interaction was identified. We demonstrate that binding of the 30 kDa fibronectin fragment to the repeat region of SfbI protein co-operatively activates the adjacent SfbI spacer domain to bind the 45 kDa fibronectin fragment. The biological consequence arising from this novel mode of fibronectin targeting was analysed in eukaryotic cell invasion assays. The repeat region of SfbI protein is mediating adherence and constitutes a prerequisite for subsequent invasion, whereas the SfbI spacer domain efficiently triggers the invasion process of streptococci into the eukaryotic cell. Thus, we were able to dissect bacterial adhesion from invasion by manipulating one protein. SfbI protein therefore represents a highly evolved prokaryotic molecule that exploits the host factor fibronectin not only for extracellular targeting but also for its subsequent activation that leads to efficient cellular invasion. 相似文献
12.
Tulloch PA Lawrence LJ McKern NM Robinson CP Bentley JD Cosgrove L Ivancic N Lovrecz GO Siddle K Ward CW 《Journal of structural biology》1999,125(1):11-18
The insulin receptor (IR) is a four-chain, transmembrane dimer held together by disulfide bonds. To gain information about the molecular envelope and the organization of its domains, single-molecule images of the IR ectodomain and its complexes with three Fabs have been analyzed by electron microscopy. The data indicate that the IR ectodomain resembles a U-shaped prism of approximate dimensions 90 x 80 x 120 A. The width of the cleft (assumed membrane-distal) between the two side arms is sufficient to accommodate ligand. Fab 83-7, which recognizes the cys-rich region of IR, bound halfway up one end of each side arm in a diametrically opposite manner, indicating a twofold axis of symmetry normal to the membrane surface. Fabs 83-14 and 18-44, which have been mapped respectively to the first fibronectin type III domain (residues 469-592) and residues 765-770 in the insert domain, bound near the base of the prism at opposite corners. These images, together with the data from the recently determined 3D structure of the first three domains of the insulin-like growth factor type I receptor, suggest that the IR dimer is organized into two layers with the L1/cys-rich/L2 domains occupying the upper (membrane distal) region of the U-shaped prism and the fibronectin type III domains and the insert domains located predominantly in the membrane-proximal region. 相似文献
13.
Huang D Eudy JD Uzvolgyi E Davis JR Talmadge CB Pretto D Weston MD Lehman JE Zhou M Seemayer TA Ahmad I Kimberling WJ Sumegi J 《Genomics》2002,80(2):195-203
Usher syndrome type IIA (MIM: 27601) is an autosomal recessive disorder characterized by moderate to severe congenital deafness and progressive retinitis pigmentosa. We recently identified the human Usher syndrome type IIA gene (USH2A) on chromosome 1q41, which encodes a protein possessing 10 laminin epidermal growth factor and four fibronectin type 3 domains, both commonly observed in extracellular matrix proteins. To gain insight into the pathogenesis of Usher syndrome type IIA, we isolated and characterized the murine (Ush2a) and rat (rat Ush2a) orthologs of human USH2A. We mapped mouse Ush2a by fluorescence in situ hybridization to mouse chromosome 1 in the region syntenic to human chromosome 1q41. Rat Ush2a has been localized by radiation hybrid mapping to rat chromosome 13 between d13rat49 and d13rat76. The mouse and rat genes, similar to human USH2A, are expressed primarily in retina and cochlea. Mouse Ush2a encodes a 161-kDa protein that shows 68% identity and 9% similarity to the human USH2A protein. Rat Ush2a encodes a 167-kDa protein with 64% identity and 10% similarity to the human protein and 81% identity and 5% similarity to the mouse USH2A protein. The predicted amino acid sequence of the mouse and rat proteins, like their human counterpart, contains a leader sequence, an amino-terminal globular domain, 10 laminin epidermal growth factor domains, and four carboxy-terminal fibronectin type III motifs. With in situ hybridization, we compared the cellular expression of the USH2A gene in rat, mouse, and human retinas. USH2A mRNA in the adult rat, mouse, and human is expressed in the cells of the outer nuclear layer of the retina, one of the target tissues of the disease. In the developing rat retina, Ush2a mRNA expression appears in the neuroepithelium at embryonic day 17. 相似文献
14.
Expression and analysis of COOH-terminal deletions of the human thrombospondin molecule 总被引:4,自引:1,他引:3
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Thrombospondin (TSP) is a homotrimeric extracellular glycoprotein with a subunit molecular mass of 140 kD. The subunits have a modular or domain-like structure and are held together by interchain disulphide bonds. A number of domains have been identified including those for the binding of collagen, fibrinogen, and heparin. Due to the trimeric form of the TSP molecule, the various domains are trivalent in nature and this contributes to the ability of TSP to mediate cell-substrate interactions. Indeed, TSP has recently been shown not only to promote cell adhesion but also to be intimately involved in cell growth and migration. The adhesive function of TSP is attributable to the "solid-phase" or matrix-bound form of the molecule. There is some evidence that the heparin-binding domain mediates incorporation of soluble TSP into the insoluble matrix form. The heparin-binding domain of TSP is a compact globular amino-terminal moiety that contains two clusters of basic amino acids and a single intrachain disulphide bond. To delineate the role of the heparin-binding domain in matrix assembly and to define further the precise region of interchain disulphide bonding that results in trimer formation, we have expressed deleted forms of the cDNA encoding TSP in SV-40-transformed. African green monkey kidney cells. The proteins synthesized from the various deleted TSP cDNAs were examined for (a) secretion into the culture medium and incorporation into the extracellular matrix; (b) binding to heparin-Sepharose; (c) immunoprecipitability by a conformation-specific monoclonal antibody; and (d) ability to form trimers. This analysis allowed us to draw the following conclusions. (a) A 218 amino acid NH2-terminal protein that preserves the intrachain disulphide bridge of the heparin-binding domain is capable of binding to heparin-Sepharose and incorporating into the extracellular matrix. (b) A shorter 164 amino acid NH2-terminal peptide that does not contain the intrachain disulphide bridge of the heparin-binding domain is neither able to bind to heparin-Sepharose nor able to incorporate into the extracellular matrix. (c) The region of interchain disulphide bridging necessary for trimer assembly resides within a cluster of seven cysteine residues immediately adjacent to the heparin-binding domain. 相似文献
15.
The complete primary structure of type XII collagen shows a chimeric molecule with reiterated fibronectin type III motifs, von Willebrand factor A motifs, a domain homologous to a noncollagenous region of type IX collagen, and short collagenous domains with an Arg-Gly-Asp site 总被引:3,自引:2,他引:3
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M Yamagata K M Yamada S S Yamada T Shinomura H Tanaka Y Nishida M Obara K Kimata 《The Journal of cell biology》1991,115(1):209-221
Extracellular matrix molecules are generally categorized as collagens, elastin, proteoglycans, or other noncollagenous structural/cell interaction proteins. Many of these extracellular proteins contain distinctive repetitive modules, which can sometimes be found in other proteins. We describe the complete primary structure of an alpha 1 chain of type XII collagen from chick embryonic fibroblasts. This large, structurally chimeric molecule identified by cDNA analysis combines previously unrelated molecular domains into a single large protein 3,124 residues long (approximately 340 kD). The deduced chicken type XII collagen sequence starts at the amino terminus with one unit of the type III motif of fibronectin, which is followed by one unit homologous to the von Willebrand factor A domain, then one more fibronectin type III module, a second A domain from von Willebrand factor, 6 units of type III motif and a third A domain, 10 consecutive units of type III motif and a fourth A domain, a domain homologous to the NC4 domain peptide of type IX collagen, and finally two short collagenous regions previously described as part of the partially sequenced collagen type XII molecule; an Arg-Gly-Asp potential cell adhesive recognition sequence is present in a hydrophilic region at the terminus of one collagenous domain. Antibodies raised to type XII collagen synthesized in a bacterial expression system recognized not only previously reported bands (220 kD et cetera) in tendons, but also bands with apparently different molecular sizes in fibroblasts and 4-d embryos. The antibodies stained a wide variety of extracellular matrices in embryos in patterns distinct from those of fibronectin or interstitial collagens. They prominently stained extracellular matrix associated with certain neuronal tissues, such as axons from dorsal root ganglia and neural tube. These studies identify a novel chimeric type of molecule that contains both adhesion molecule and collagen motifs in one protein. Its structure blurs current classification schemes for extracellular proteins and underscores the potentially large diversity possible in these molecules. 相似文献
16.
Rapid evolution by positive Darwinian selection in the extracellular domain of the abundant lymphocyte protein CD45 in primates 总被引:5,自引:0,他引:5
CD45, encoded by PTPRC in humans, is the most abundantly expressed protein on the surface of many lymphocytes. We investigated whether the extracellular region of CD45 was under positive selection in Old World primates, and whether there was differential selection across this region, particularly on exons that were involved in alternative splicing and those that were not alternatively spliced. The results show extraordinarily strong and consistent positive Darwinian selection on the extracellular part of CD45 throughout the evolution of Old World monkeys, apes and humans. Positive selection is concentrated in exons 9 and 14, which code for the previously neglected linker and fibronectin III domains. These exons have a high rate of evolution at nonsynonymous sites that is roughly twice as high as that of the intronic rate in this gene. In contrast, alternatively spliced exons 4-6, which code for the variable domains, are under weaker positive selection and are evolving more slowly than the intronic rate. These data provide a striking example of positive selection in a well-known gene that should provide an impetus for further functional studies to elucidate its species-specific function. 相似文献
17.
Oberhauser AF Badilla-Fernandez C Carrion-Vazquez M Fernandez JM 《Journal of molecular biology》2002,319(2):433-447
Mechanically induced conformational changes in proteins such as fibronectin are thought to regulate the assembly of the extracellular matrix and underlie its elasticity and extensibility. Fibronectin contains a region of tandem repeats of up to 15 type III domains that play critical roles in cell binding and self-assembly. Here, we use single-molecule force spectroscopy to examine the mechanical properties of fibronectin (FN) and its individual FNIII domains. We found that fibronectin is highly extensible due to the unfolding of its FNIII domains. We found that the native FNIII region displays strong mechanical unfolding hierarchies requiring 80 pN of force to unfold the weakest domain and 200 pN for the most stable domain. In an effort to determine the identity of the weakest/strongest domain, we engineered polyproteins composed of an individual domain and measured their mechanical stability by single-protein atomic force microscopy (AFM) techniques. In contrast to chemical and thermal measurements of stability, we found that the tenth FNIII domain is mechanically the weakest and that the first and second FNIII domains are the strongest. Moreover, we found that the first FNIII domain can acquire multiple, partially folded conformations, and that their incidence is modulated strongly by its neighbor FNIII domain. The mechanical hierarchies of fibronectin demonstrated here may be important for the activation of fibrillogenesis and matrix assembly. 相似文献
18.
A deletion in the gene encoding the CD45 antigen in a patient with SCID 总被引:12,自引:0,他引:12
Tchilian EZ Wallace DL Wells RS Flower DR Morgan G Beverley PC 《Journal of immunology (Baltimore, Md. : 1950)》2001,166(2):1308-1313
19.
The macrophage mannose receptor is the prototype for a family of receptors each having an extracellular region consisting of an N-terminal cysteine-rich domain related to the R-type carbohydrate-recognition domain of ricin, a fibronectin type II domain and eight to ten domains related to C-type carbohydrate-recognition domains. The mannose receptor acts as a molecular scavenger, clearing harmful glycoconjugates or micro-organisms through recognition of their defining carbohydrate structures. Cell-adhesion assays, as well as collagen-binding assays, have now been used to show that the mannose receptor can also bind collagen and that the fibronectin type II domain mediates this activity. Neither of the two types of sugar-binding domain in the receptor is involved in collagen binding. Fibroblasts expressing the mannose receptor adhere to type I, type III and type IV collagens, but not to type V collagen, and the adherence is inhibited by isolated mannose receptor fibronectin type II domain. The fibronectin type II domain shows the same specificity for collagen as the whole receptor, binding to type I, type III and type IV collagens. This is the first activity assigned to the fibronectin type II domain of the mannose receptor. The results suggest additional roles for this multifunctional receptor in mediating collagen clearance or cell-matrix adhesion. 相似文献
20.
《Matrix biology》2014
The extracellular matrix (ECM) is a major mediator of multi-cellularity in the metazoa. Multiple ECM proteins are conserved from sponges to human, raising questions about the evolutionary origin of ECM. Choanoflagellates are the closest unicellular relatives of the metazoa and proteins with domains characteristic of metazoan ECM proteins have been identified from the genome-predicted proteome of the choanoflagellate Monosiga brevicollis. However, a systematic analysis of M. brevicollis secretory signal peptide-containing proteins with ECM domains has been lacking. We analysed all predicted secretory signal-peptide-containing proteins of M. brevicollis for ECM domains. Nine domains that are widespread in metazoan ECM proteins are represented, with EGF, fibronectin III, laminin G, and von Willebrand Factor_A domains being the most numerous. Three proteins contain more than one category of ECM domain, however, no proteins correspond to the domain architecture of metazoan ECM proteins. The fibronectin III domains are all present within glycoside hydrolases and none contain an integrin-binding motif. Glycosaminoglycan-binding motifs identified in animal thrombospondin type 1 domains are conserved in some M. brevicollis representatives of this domain, whereas there is little evidence of conservation of glycosaminoglycan-binding motifs in the laminin G domains. The identified proteins were compared with the predicted secretory ECM domain-containing proteins of the integrin-expressing filasterean, Capsaspora owczarzaki. C. owczarzaki encodes a smaller number of secretory, ECM domain-containing proteins and only EGF, fibronectin type III and laminin G domains are represented. The M. brevicollis and C. owczarzaki proteins have distinct domain architectures and all proteins differ in their domain architecture to metazoan ECM proteins. These identifications provide a basis for future experiments to validate the extracellular location of these proteins and uncover their functions in choanoflagellates and C. owczarzaki. The data strengthen the model that ECM proteins are metazoan-specific and evolved as innovations in the last common metazoan ancestor. 相似文献