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PubMed1998

Exit of major histocompatibility complex class II-invariant chain p35 complexes from the endoplasmic reticulum is modulated by phosphorylation.

The Iip35 isoform of the major histocompatibility complex (MHC) class II-associated invariant chain (Ii) contains an endoplasmic reticulum (ER) targeting motif, but in B cell lines the ER retention is ineffective and a fraction of Iip35 is transported through the Golgi complex associated with class II molecules. We found Iip35 (but not Iip33, the major form of Ii) to be phosphorylated in B cell lines, as well as in transfected HeLa cells. The phosphorylation of Iip35 was found to be necessary for the exit of Iip35-class II complexes out of the ER. This requirement suggests that phosphorylation may change the interaction with factors responsible for ER retention/retrieval, and we did find that phosphorylated Iip35 associates with 14-3-3 proteins, a family of adaptor proteins that are involved in coordinating signal transduction pathways. This finding raises the intriguing possibility that the exit of Ii-class II complexes from the ER is regulated by intracellular signaling events.

14-3-3 Proteins↗

PubMed1996

Sialomucin complex, a heterodimeric glycoprotein complex. Expression as a soluble, secretable form in lactating mammary gland and colon.

Ascites 13762 rat mammary adenocarcinoma cells express abundantly on their cell surfaces a heterodimeric glycoprotein complex composed of a sialomucin ascites sialoglycoprotein (ASGP)-1 and a transmembrane subunit ASGP-2. The latter, which contains two epidermal growth factor-like domains, binds the receptor tyrosine kinase p185(neu), suggesting that the complex is bifunctional as well as heterodimeric. Immunoblot analyses using monoclonal antibodies prepared against the complex demonstrate high levels of expression in rat lactating mammary gland and colon. Immunolocalization studies with anti-ASGP-2 indicate that ASGP-2 is present in these two tissues in the apical regions of secretory epithelial cells. Both mammary gland and colon contain a soluble, secretable form of ASGP-2, which is not found in the ascites cells; milk and mammary gland also have the membrane form. Immunoblot analyses using a COOH-terminal-specific polyclonal antibody indicate that the soluble form of ASGP-2 is missing its COOH-terminal domains. Both the soluble and membrane forms of ASGP-2 are similar to the membrane-associated form from the 13762 adenocarcinoma with respect to Mr, antigenicity, and association with ASGP-1. The presence of ASGP-1 in milk suggests that it is a candidate for the uncharacterized high Mr milk mucin, MUCX. ASGP-2 expression is up-regulated in mammary gland during pregnancy, because it is undetectable in virgin and early pregnant rats but abundant in the gland from late pregnant and lactating animals. However, compared with the lactating mammary gland, the 13762 ascites cells overexpress ASGP-2 by more than 100-fold, which may contribute to their malignancy. These combined results indicate that sialomucin complex is a unique secreted product in the mammary gland and colon, whose behavior is different from that in the mammary ascites tumors, and which may play important roles in mammary and intestinal physiology.

Animals↗

PubMed1997

Decreased endosomal delivery of major histocompatibility complex class II-invariant chain complexes in dynamin-deficient cells.

Major histocompatibility complex class II molecules are heterodimeric cell surface molecules which acquire antigenic peptides in the endosomal/lysosomal system. Invariant chain (Ii), a third chain which is associated with class II molecules intracellularly mediates the endosomal targeting, but it is debated whether class II molecules reach the endosomal system mainly from the trans-Golgi network or via the cell surface. Dynamin is a cytosolic GTPase which is necessary for the formation of clathrin-coated vesicles from the plasma membrane, but which is not required for vesicle formation from the trans-Golgi network. Here we have used HeLa cells expressing a dominant negative form of dynamin to show that inhibition of clathrin-mediated uptake from the plasma membrane leads to accumulation of transfected Ii-class II complexes at the cell surface, while delivery of such complexes to endosomes/lysosomes is decreased. Our data therefore suggest that in this experimental system the majority of Ii-class II complexes traverse the cell surface before they reach the endosomal system.

Antigens, Differentiation, B-Lymphocyte↗

PubMed1997

Alpha-catenin can form asymmetric homodimeric complexes and/or heterodimeric complexes with beta-catenin.

The cadherin-based transmembrane cell-cell adhesive complex is thought to be composed of a cadherin molecule, a beta-catenin, and an alpha-catenin, which connects the complex to the cytoskeleton. The precise stoichiometry of this complex remains uncertain. We have used a series of recombinant molecules and biophysical techniques to assess the multimeric state of human alpha- and beta-catenin in vitro and then visualized them by electron microscopy after rotary shadowing. Calculated solution molecular masses are 213 kDa for alpha-catenin, 73 kDa for beta-catenin, and 186 kDa for both. This suggests that alpha-catenin exists as a homodimer in solution, beta-catenin is a monomer, and when both are present, they form alpha/beta-catenin heterodimers. Co-precipitation and surface plasmon resonance assays localize the site of alpha-catenin dimerization to the NH2-terminal 228 amino acids. This region encompasses a high-affinity (Kd = 100 nM) binding site for beta-catenin that lies between residues 54 and 157. We anticipate that the oligomeric state of alpha-catenin and the relative stoichiometry of the components in the membrane adhesion complex will be dynamic and regulated by beta-catenin, cell adhesion, and probably other factors as well.

Binding Sites↗

PubMed1999

Modification of the T cell antigen receptor (TCR) complex by UDP-glucose:glycoprotein glucosyltransferase. TCR folding is finalized convergent with formation of alpha beta delta epsilon gamma epsilon complexes.

Most T lymphocytes express on their surfaces a multisubunit receptor complex, the T cell antigen receptor (TCR) containing alpha, beta, gamma, delta, epsilon, and zeta molecules, that has been widely studied as a model system for protein quality control. Although the parameters of TCR assembly are relatively well established, little information exists regarding the stage(s) of TCR oligomerization where folding of TCR proteins is completed. Here we evaluated the modification of TCR glycoproteins by the endoplasmic reticulum folding sensor enzyme UDP-glucose:glycoprotein glucosyltransferase (GT) as a unique and sensitive indicator of how TCR subunits assembled into multisubunit complexes are perceived by the endoplasmic reticulum quality control system. These results demonstrate that all TCR subunits containing N-glycans were modified by GT and that TCR proteins were differentially reglucosylated during their assembly with partner TCR chains. Importantly, these data show that GT modification of most TCR subunits persisted until assembly of CD3alpha beta chains and formation of CD3-associated, disulfide-linked alpha beta heterodimers. These studies provide a novel evaluation of the folding status of TCR glycoproteins during their assembly into multisubunit complexes and are consistent with the concept that TCR folding is finalized convergent with formation of alpha beta delta epsilon gamma epsilon complexes.

Animals↗

PubMed2000

Medial Golgi but not late Golgi glycosyltransferases exist as high molecular weight complexes. Role of luminal domain in complex formation and localization.

To investigate the organization of Golgi glycosyltransferases and their mechanism of localization, we have compared the properties of a number of medial and late acting Golgi enzymes. The medial Golgi enzymes, N-acetylglucosaminyltransferase I and II (GnTI and GnTII) required high salt for solubilization and migrated as high molecular weight complexes on sucrose density gradients. In contrast, the late acting Golgi enzymes, beta1,4-galactosyltransferase and alpha1, 2-fucosyltransferase, were readily solubilized in low salt and migrated as monomers/dimers by sucrose density gradient centrifugation. Analysis of membrane-bound GnTI chimeras indicates that the formation of high molecular weight complexes does not require the transmembrane domain and cytoplasmic tail sequences of GnTI. Furthermore, a soluble form of GnTI, containing the stem region and catalytic domain, accumulated in the Golgi prior to secretion, in contrast to beta1,4-galactosyltransferase. Soluble GnTI, which also associated with high molecular weight complexes, was comparable with membrane-bound GnTI in its ability to glycosylate newly synthesized glycoproteins in vivo. Mutation of charged residues within the stem region of GnTI, known to be important for "kin recognition", had no effect on the efficiency of Golgi localization, the inclusion into high molecular weight complexes, nor functional activity in vivo. The differences in behavior between the medial and late acting Golgi enzymes may contribute to their differential localization and their ability to glycosylate efficiently in the correct Golgi subcompartment.

Animals↗

PubMed2000

Regulation of complex formation of POB1/epsin/adaptor protein complex 2 by mitotic phosphorylation.

RalBP1 and POB1, the downstream molecules of small GTP-binding protein Ral, are involved in receptor-mediated endocytosis together with Epsin and Eps15. The regulation of assembly of the complex of these proteins was examined. RalBP1, POB1, Epsin, and Eps15 formed a complex with alpha-adaptin of AP-2 in Chinese hamster ovary cells, but the formation was reduced in mitotic phase. RalBP1, POB1, Epsin, and Eps15 were all phosphorylated in mitotic phase. The phosphorylated forms of POB1 and Epsin were recognized by the antibody MPM2, which is known to detect mitotic phosphoproteins. POB1 and Epsin were phosphorylated by p34(cdc2) kinase in vitro. Their phosphorylation sites (Ser(411) of POB1 and Ser(357) of Epsin) were determined. Phosphorylated Epsin and Epsin(S357D) formed a complex with alpha-adaptin less efficiently than wild type Epsin. Although the EH domain of POB1 bound directly to Epsin, phosphorylation of Epsin inhibited the binding. Furthermore, Epsin(S357D) but not Epsin(S357A) lost the effect of Epsin on the insulin-dependent endocytosis. These results suggest that phosphorylation of Epsin in mitotic phase inhibits receptor-mediated endocytosis by disassembly of its complex with POB1 and alpha-adaptin.

Adaptor Proteins, Vesicular Transport↗

PubMed2001

Identification of the high affinity binding site in transforming growth factor-beta involved in complex formation with alpha 2-macroglobulin. Implications regarding the molecular mechanisms of complex formation between alpha 2-macroglobulin and growth factors, cytokines, and hormones.

The biological activities of transforming growth factor-beta isoforms (TGF-beta(1,2)) are known to be modulated by alpha(2)-macroglobulin (alpha(2)M). alpha(2)M forms complexes with numerous growth factors, cytokines, and hormones, including TGF-beta. Identification of the binding sites in TGF-beta isoforms responsible for high affinity interaction with alpha(2)M many unravel the molecular basis of the complex formation. Here we demonstrate that among nine synthetic pentacosapeptides with overlapping amino acid sequences spanning the entire TGF-beta(1) molecule, the peptide (residues 41-65) containing Trp-52 exhibited the most potent activity in inhibiting the formation of complexes between (125)I-TGF-beta(1) and activated alpha(2)M (alpha(2)M*) as determined by nondenaturing polyacrylamide gel electrophoresis and by plasma clearance in mice. TGF-beta(2) peptide containing the homologous sequence and Trp-52 was as active as the TGF-beta(1) peptide, whereas the corresponding TGF-beta(3) peptide lacking Trp-52, was inactive. The replacement of the Trp-52 with alanine abolished the inhibitory activities of these peptides. (125)I-TGF-beta(3), which lacks Trp-52, bound to alpha(2)M* with an affinity lower than that of (125)I-TGF-beta(1). Furthermore, unlabeled TGF-beta(3) and the mutant TGF-beta(1)W52A, in which Trp-52 was replaced with alanine, were less potent than unlabeled TGF-beta(1) in blocking I(125)-TGF-beta(1) binding to alpha(2)M*. TGF-beta(1) and TGF-beta(2) peptides containing Trp-52 were also effective in inhibiting I(125)-nerve growth factor binding to alpha(2)M*. Tauhese results suggest that Trp-52 is involved in high affinity binding of TGF-beta to alpha(2)M*. They also imply that TGF-beta and other growth factors/cytokines/hormones may form complexes with alpha(2)M* via a common mechanism involving the interactions between topologically exposed Trp and/or other hydrophobic residues and a hydrophobic region in alpha(2)M*.

Amino Acid Sequence↗

PubMed2005

Structure of the complex between plastocyanin and cytochrome f from the cyanobacterium Nostoc sp. PCC 7119 as determined by paramagnetic NMR. The balance between electrostatic and hydrophobic interactions within the transient complex determines the relative orientation of the two proteins.

The complex between cytochrome f and plastocyanin from the cyanobacterium Nostoc has been characterized by NMR spectroscopy. The binding constant is 16 mM(-1), and the lifetime of the complex is much less than 10 ms. Intermolecular pseudo-contact shifts observed for the plastocyanin amide nuclei, caused by the heme iron, as well as the chemical-shift perturbation data were used as the sole experimental restraints to determine the orientation of plastocyanin relative to cytochrome f with a precision of 1.3 angstroms. The data show that the hydrophobic patch surrounding tyrosine 1 in cytochrome f docks the hydrophobic patch of plastocyanin. Charge complementarities are found between the rims of the respective recognition sites of cytochrome f and plastocyanin. Significant differences in the relative orientation of both proteins are found between this complex and those previously reported for plants and Phormidium, indicating that electrostatic and hydrophobic interactions are balanced differently in these complexes.

Animals↗

PubMed2006

Hierarchical network between the components of the multi-tRNA synthetase complex: implications for complex formation.

The macromolecular tRNA synthetase complex consists of nine different enzymes and three non-enzymatic factors. This complex was recently shown to be a novel signalosome, since many of its components are involved in signaling pathways in addition to their catalytic roles in protein synthesis. The structural organization and dynamic relationships of the components of the complex are not well understood. Here we performed a systematic depletion analysis to determine the effects of structural intimacy and the turnover of the components. The results showed that the stability of some components depended on their neighbors. Lysyl-tRNA synthetase was most independent of other components for its stability whereas it was most required for the stability of other components. Arginyl- and methionyl-tRNA synthetases had the opposite characteristics. Thus, the systematic depletion of the components revealed the functional reason for the complex formation and the assembly pattern of these multi-functional enzymes and their associated factors.

Amino Acyl-tRNA Synthetases↗

PubMed1996

X-ray studies on crystalline complexes involving amino acids and peptides. XXXI. Effect of chirality on ionization state, stoichiometry and aggregation in the complexes of oxalic acid with L- and DL-histidine.

Crystals of the oxalic acid complex of L-histidine (orthorhombic P2(1)2(1)2(1); a = 5.535(4), b = 6.809(4), c = 26.878(3) A; R = 3.6% for 1188 observed reflections) contain histidine molecules and semi-oxalate ions in the 1:1 ratio, while the ratio is 1:2 in the crystals of the DL-histidine complex (monoclinic P2(1)lc; a = 6.750(7), b = 10.139(2), c = 19.352(2) A, beta = 90.8 degrees; R = 3.7% for 3176 observed reflections). The histidine molecule in the latter has an unusual ionization state with positively charged amino and imidazole groups and a neutral carboxyl group. The molecule has the sterically least favourable allowed conformation with the side chain imidazole ring staggered between the alpha-amino and the alpha- carboxyl (carboxylate) groups, in both the structures. The unlike molecules aggregate into separate alternating layers in both of them. There are elements of similarity in the aggregation patterns in the semi-oxalate layers in the two complexes, but the patterns in the amino acid layers are entirely different. Interestingly, the crystal structure of L-histidine semi-oxalate has broad similarities with that of DL-histidine = glycolate, demonstrating how broad features of aggregation could be retained inspite of changes in chirality and composition. The unusual ionization state of the amino acid molecule in the DL-histidine complex is reflected in a hitherto unobserved aggregation pattern in its crystal structure.

Crystallography, X-Ray↗

PubMedDate not supplied

Mixed cobalt(III) complexes with aromatic amino acids and diamine. Part IV. Influence of noncovalent intra-and interligand interactions on rotamer population of the S-phenylalaninato and S-tyrosinato side groups in (1,2-diaminoethane)bis-(S-aminocarboxylato)cobalt(III) complexes.

Rotamer population of S-tyrosinato and S-phenylalaninato ligands side groups in diastereomers of (1,2-diaminoethane)bis-(S-aminocarboxylato)cobalt(III) complexes is calculated by vicinal alpha and beta proton coupling constant analysis. The effect of noncovalent intra- and interligand interactions on the population of rotamers in D20 solution is discussed. It has been established that in all the complexes investigated the most abundant is rotamer t, in which aromatic voluminous moiety and carboxylic group are in an anti position. In almost all complexes the lowest content is of rotamer g, in which these two groups are in the nearest position. Relatively high population of rotamer h in complex 5 tyr, in spite of high steric hindrances, is due to intra- and interligand NH...pi interactions.

Journal Article↗

PubMed2002

Polylysine and polyornithine gene transfer complexes: a study of complex stability and cellular uptake as a basis for their differential in-vitro transfection efficiency.

Gene transfer vectors formed between the cationic polyamino acid, poly-(L)-omithine (PLO) and plasmid DNA (pDNA) have demonstrated superior transfection efficiency (up to x 10-fold) compared to equivalent polylysine-based systems in-vitro. The mechanism(s) underlying this observation remains to be elucidated. We previously reported no significant difference in colloidal particle size or zeta potential of polycation/pDNA complexes formed with poly-(L)-lysine (PLL), poly-(D)-lysine (PDL) or PLO. Here we report spectrofluorometric analysis indicating that PLO condenses pDNA at lower charge (+/-) ratios than PLL or PDL (cf. 0.8:1, 1.2:1 and 1.5:1). Moreover, PLO/pDNA complexes proved more stable to disruption by the polyanions, poly-(L)-aspartic acid (PAA) and heparin. There were no qualitative differences in the ability of the polycations to protect complexed pDNA from enzymatic degradation both in the presence and in the absence of polyanions. The superior transfection efficiency of PLO/pDNA complexes did not appear to be mediated by an increased cellular delivery of pDNA. The data suggests a greater affinity of PLO for pDNA as an important parameter for the observed superior in-vitro transfection efficiency.

Cell Line↗

PubMed1999

Function of alpha3beta1-tetraspanin protein complexes in tumor cell invasion. Evidence for the role of the complexes in production of matrix metalloproteinase 2 (MMP-2).

Tumor cell migration through the three- dimensional extracellular matrix (ECM) environment is an important part of the metastatic process. We have analyzed a role played by the integrin-tetraspanin protein complexes in invasive migration by culturing MDA-MB-231 cells within Matrigel. Using time-lapse video recording, we demonstrated that the Matrigel-embedded cells remain round and exhibit only limited ability for migration by extending short, highly dynamic pseudopodia. The alpha3beta1-tetraspanin protein complexes were clustered on the thin microvilli-like protrusions extending from both the main cell body and pseudopodia. Ligation of the alpha3beta1-tetraspanin protein complexes with monoclonal antibodies specifically stimulates production of matrix metalloproteinase 2 (MMP-2) and induces formation of long invasive protrusions within Matrigel. Accordingly, treatment with the monoclonal antibodies to various tetraspanin proteins and to the alpha3 integrin subunit increases invasive potential of the MDA-MB-231 cells in the Matrigel-penetration assay. A specific inhibitor of phosphoinositide 3-kinase (PI3K), LY294002, negated the effect of the monoclonal antibodies on the morphology of the Matrigel-embedded cells and on production of MMP-2. Interestingly, broad-spectrum inhibitors of protein tyrosine kinases (genistein) and protein tyrosine phosphatases (orthovanadate), and actin filament stabilizing compound (jasplakinolide), also block protrusive activity of the Matrigel-embedded cells but have no effect on the production of MMP-2. These results indicate that alpha3beta1-tetraspanin protein complexes may control invasive migration of tumor cells by using at least two PI3K-dependent signaling mechanisms: through rearrangement of the actin cytoskeleton and by modulating the MMP-2 production.

Actins↗

PubMed1958

Immunoreactions involving platelets. I. A steric and kinetic model for formation of a complex from a human antibody, quinidine as a haptene, and platelets; and for fixation of complement by the complex.

A steric and kinetic model for the sequence and mechanism of reactions leading to formation of a complex from an antibody, a haptene (quinidine), and a cell membrane (platelets), and to fixation of complement by the complex was deduced from the effects of varying the initial concentration of each component of the complex on the amount of complement fixed, from kinetic aspects of the sequential reactions, and from other chemical and physical properties of the various components involved. Theoretical results calculated using equations based on the model, which were derived by Dr. Terrell L. Hill, were similar in all respects to experimental results. Results of this study were consistent with the possibilities that the protein moiety of a haptenic antigen involved in development of an antibody which attaches to a cell is not necessarily a component of the cell, and that the cell reacts with the antibody by virtue of having a surface favorable for non-specific adsorption of certain haptene-antibody complexes.

Antibodies↗

PubMed1993

Peptide-major histocompatibility complex class II complexes with mixed agonist/antagonist properties provide evidence for ligand-related differences in T cell receptor-dependent intracellular signaling.

Clonal activation of CD4+ and CD8+ T lymphocytes depends on binding of peptide-major histocompatibility complex (MHC) molecule complexes by their alpha/beta receptors, eventually resulting in sufficient aggregation to initiate second messenger generation. The nature of intracellular signals resulting from such T cell receptor (TCR) occupancy is believed to be independent of the specific structure of the ligand being bound, and to vary quantitatively, not qualitatively, with the concentration of ligand offered and the affinity of the receptor for the peptide-MHC molecule complex. In contrast to the expectations of this model, the analysis of the response of a T helper type 1 clone to mutant E alpha E beta k molecules in the absence or presence of a peptide antigen revealed that peptide inhibited the interleukin 2 (IL-2) response to an otherwise allostimulatory mutant form of this MHC class II molecule. The inhibition was not due to competition for formation of alloantigen, it required TCR recognition of peptide-mutant MHC molecule complexes, and it decreased IL-2 production without affecting receptor-dependent IL-3, IL-2 receptor alpha, or size enlargement responses. This preferential reduction in IL-2 secretion could be correlated with the costimulatory signal dependence of this cytokine response, but could not be overcome by crosslinking the CD28 molecule on the T cell. These results define a new class of TCR ligands with mixed agonist/antagonist properties, and point to a ligand-related variation in the quality of clonotypic receptor signaling events or their integration with other signaling processes. It was also found that a single TCR ligand showed greatly different dose thresholds for the elicitation of distinct effector responses from a cloned T cell population. The observations that changes in ligand structure can result in qualitative alterations in the effects of receptor occupancy and that quantitative variations in ligand density can be translated into qualitative differences in T cell responses have important implications for models of intrathymic selection and control of the results of active immunization.

Amino Acid Sequence↗

PubMed1994

The V beta complementarity determining region 1 of a major histocompatibility complex (MHC) class I-restricted T cell receptor is involved in the recognition of peptide/MHC I and superantigen/MHC II complex.

We investigated the role of the complementarity determining region 1 (CDR1) of T cell receptor (TCR) beta chain both in antigen/major histocompatibility complex I (MHC I) and in superantigen (SAg)/MHC II complex recognition. Residues 26 to 31 of the V beta 10 domain of a TCR derived from an H-2Kd-restricted cytotoxic clone were individually changed to alanine, using site-directed mutagenesis, and the mutated TCR beta chains were transfected along with the wild-type TCR alpha chain into a TCR alpha-beta-T hydridoma. These mutations affected antigen/H-2Kd complex recognition, although to a different extent, as estimated by interleukin 2 production. Certain mutations also affected differently the recognition of two Staphylococcal toxins, exfoliative toxin and Staphylococcal enterotoxin C2, presented by HLA-DR1. Whereas mutation of residues D30 or T31 affect the recognition of both toxins, residues T26, L27, and H29 are critical for the recognition of only one of the SAgs. These observations demonstrate the participation of the CDR1 region in the recognition of peptide/MHC class I as well as SAg/MHC II complexes.

Alanine↗

PubMed2002

Evidence that ternary complex (eIF2-GTP-tRNA(i)(Met))-deficient preinitiation complexes are core constituents of mammalian stress granules.

Environmental stress-induced phosphorylation of eIF2alpha inhibits protein translation by reducing the availability of eIF2-GTP-tRNA(i)Met, the ternary complex that joins initiator tRNA(Met) to the 43S preinitiation complex. The resulting untranslated mRNA is dynamically routed to discrete cytoplasmic foci known as stress granules (SGs), a process requiring the related RNA-binding proteins TIA-1 and TIAR. SGs appear to be in equilibrium with polysomes, but the nature of this relationship is obscure. We now show that most components of the 48S preinitiation complex (i.e., small, but not large, ribosomal subunits, eIF3, eIF4E, eIF4G) are coordinately recruited to SGs in arsenite-stressed cells. In contrast, eIF2 is not a component of newly assembled SGs. Cells expressing a phosphomimetic mutant (S51D) of eIF2alpha assemble SGs of similar composition, confirming that the recruitment of these factors is a direct consequence of blocked translational initiation and not due to other effects of arsenite. Surprisingly, phospho-eIF2alpha is recruited to SGs that are disassembling in cells recovering from arsenite-induced stress. We discuss these results in the context of a translational checkpoint model wherein TIA and eIF2 are functional antagonists of translational initiation, and in which lack of ternary complex drives SG assembly.

Animals↗