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Results for “peptide binding”

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PubMed2000

Amyloid beta -peptide-binding alcohol dehydrogenase is a component of the cellular response to nutritional stress.

Amyloid beta-peptide-binding alcohol dehydrogenase (ABAD) is a member of the family of short chain dehydrogenase/reductases whose distinctive properties include the capacity to bind amyloid beta-peptide and enzymatic activity toward a broad array of substrates including n-isopropanol and beta-estradiol. In view of the wide substrate specificity of ABAD and its high activity on l-beta-hydroxyacyl-CoA derivatives, we asked whether it might also catalyze the oxidation of the ketone body d-3-hydroxybutyrate. This was indeed the case, and oxidation proceeded with K(m) of approximately 4.5 mm and V(max) of approximately 4 nmol/min/mg protein. When placed in medium with d-beta-hydroxybutyrate as the principal energy substrate, COS cells stably transfected to overexpress wild-type ABAD (COS/wtABAD) better maintained 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction, cellular energy charge, and morphologic phenotype compared with COS/vector cells. Using a severe model of metabolic perturbation, transgenic mice with targeted neuronal expression of ABAD subjected to transient middle cerebral artery occlusion showed strokes of smaller volume and lower neurologic deficit scores in parallel with increased brain ATP and decreased lactate, compared with nontransgenic controls. These data suggest that ABAD contributes to the protective response to metabolic stress, especially in the setting of ischemia.

3-Hydroxybutyric Acid↗

PubMed2005

RNA-mediated interaction between the peptide-binding and GTPase domains of the signal recognition particle.

The signal recognition particle (SRP) targets nascent proteins to cellular membranes for insertion or secretion by recognizing polypeptides containing an N-terminal signal sequence as they emerge from the ribosome. GTP-dependent binding of SRP to its receptor protein leads to controlled release of the nascent chain into a membrane-spanning translocon pore. Here we show that the association of the SRP with its receptor triggers a marked conformational change in the complex, localizing the SRP RNA and the adjacent signal peptide-binding site at the SRP-receptor heterodimer interface. The orientation of the RNA suggests how peptide binding and GTP hydrolysis can be coupled through direct structural contact during cycles of SRP-directed protein translocation.

Bacterial Proteins↗

PubMed2005

P. falciparum pro-histoaspartic protease (proHAP) protein peptides bind specifically to erythrocytes and inhibit the invasion process in vitro.

Plasmodium falciparum histoaspartic protease (HAP) is an active enzyme involved in haemoglobin degradation. HAP is expressed as an inactive 51-kDa zymogen and is cleaved into an active 37-kDa enzyme. It has been proposed that this kind of protease might be implicated in the parasite's invasion of erythrocytes; however, this protein's role during invasion has still to be determined. Synthetic peptides derived from the HAP precursor (proHAP) were tested in erythrocyte binding assays to identify their possible function in the invasion process. Two proHAP high-activity binding peptides (HABPs) specifically bound to erythrocytes; these peptides were numbered 30609 (101LKNYIKESVKLFNKGLTKKS120) and 30610 (121YLGSEFDNVELKDLANVLSF140 ). The binding of these two peptides was saturable, presenting nanomolar affinity constants. These peptides interacted with 26- and 45-kDa proteins on the erythrocyte surface; the nature of these receptor sites was studied in peptide binding assays using enzyme-treated erythrocytes. The HABPs showed greater than 90% merozoite invasion inhibition in in vitro assays. Goat serum containing proHAP polymeric peptide antibodies inhibited parasite invasion in vitro .

Amino Acid Sequence↗

PubMed2004

The crystal structure of Helicobacter cysteine-rich protein C at 2.0 A resolution: similar peptide-binding sites in TPR and SEL1-like repeat proteins.

Helicobacter pylori is a Gram-negative human pathogen that infects the gastric mucosa and causes an inflammatory process leading to gastritis, ulceration and cancer. Bacterial cell-surface and secreted proteins often play an important role in pathogen-host interactions and are thought to be selective mediators for the pathology of the infection. The Helicobacter cysteine-rich proteins (Hcp) represent a large family of secreted proteins that seem to be specific for microorganisms from the epsilon-subfamily of proteobacteria. Although significantly elevated levels of anti-Hcp antibodies were observed in many patients infected with H.pylori, details on the biological functions of Hcp proteins are sparse. Hcps belong to a large family of Sel1-like multi-repeat proteins. The crystal structure of HcpC was refined at 2.0 A resolution and revealed a super-helical topology composed of seven disulfide bridged alpha/alpha-repeats, an N-terminal capping helix and an extended C-terminal coil consisting of alternating hydrophobic and hydrophilic residues. In the crystal packing, the C-terminal coil interacts with the concave surface of a symmetry-related HcpC super-helix. A hydrophobic pocket and a cluster of negatively charged residues recognize the side-chains of Val290 and Lys287 from the C-terminal coil, respectively. The peptide nitrogen atom of His291 forms a short hydrogen bond with the side-chain of Asn66. The interactions seen in this crystal contact are strikingly similar to the peptide-binding modes of the Hsp70/Hsp90 organizing protein and the PEX5 receptor. The conservation of the peptide-binding mode suggests that HcpC might recognize its binding partner in a similar way.

Amino Acid Sequence↗

PubMed1999

Intragenic suppressors of Hsp70 mutants: interplay between the ATPase- and peptide-binding domains.

ATP hydrolysis and polypeptide binding, the two key activities of Hsp70 molecular chaperones, are inherent properties of different domains of the protein. The coupling of these two activities is critical because the bound nucleotide determines, in part, the affinity of Hsp70s for protein substrate. In addition, cochaperones of the Hsp40 (DnaJ) class, which stimulate Hsp70 ATPase activity, have been proposed to play an important role in promoting efficient Hsp70 substrate binding. Because little is understood about this functional interaction between domains of Hsp70s, we investigated mutations in the region encoding the ATPase domain that acted as intragenic suppressors of a lethal mutation (I485N) mapping to the peptide-binding domain of the mitochondrial Hsp70 Ssc1. Analogous amino acid substitution in the ATPase domain of the Escherichia coli Hsp70 DnaK had a similar intragenic suppressive effect on the corresponding I462T temperature-sensitive peptide-binding domain mutation. I462T protein had a normal basal ATPase activity and was capable of nucleotide-dependent conformation changes. However, the reduced affinity of I462T for substrate peptide (and DnaJ) is likely responsible for the inability of I462T to function in vivo. The suppressor mutation (D79A) appears to partly alleviate the defect in DnaJ ATPase stimulation caused by I462T, suggesting that alteration in the interaction with DnaJ may alter the chaperone cycle to allow productive interaction with polypeptide substrates. Preservation of the intragenic suppression phenotypes between eukaryotic mitochondrial and bacterial Hsp70s suggests that the phenomenon studied here is a fundamental aspect of the function of Hsp70:Hsp40 chaperone machines.

Adenosine Triphosphatases↗

PubMed1993

Position 71 in the alpha helix of the DR beta domain is predicted to influence peptide binding and plays a central role in allorecognition.

Despite all the structural and functional data that have been accumulated regarding major histocompatibility complex (MHC) class II molecules during recent years, the relative contribution of putative T cell receptor (TcR)-contacting residues and peptide-binding MHC polymorphisms to MHC-restricted and allospecific T cell responses remains a point of contention. Some authors emphasize the importance of direct interaction between the allospecific TcR and polymorphic MHC residues whereas other emphasize the role of naturally processed MHC-bound peptides. We have previously described a new HLA-DRB1 allele: DR BON (DRB1*0103). This gene differs from DRB1*0101 by six base pairs clustered in the third variable region of the second exon leading to three amino acid changes at positions 67, 70 and 71 of the beta chain of the HLA-DR molecule. To define the respective role of these residues in allorecognition, we have performed site-directed mutagenesis on the DRB1*0103 allele to create six mutants which are intermediary between the DR BON and the DR1 alleles. These mutant cDNA were expressed in mouse fibroblasts and the transfectants with the highest expression of class II molecules were used as stimulators for a panel of ten anti-DR BON and five anti-DR1 alloreactive T cell clones. We demonstrate that the residue at the peptide-binding position 71 is of paramount importance in the alloresponse of these clones. In addition some clones were sensitive to amino acid substitution at the TcR-contacting position 70, while substitution at position 67 affects very few clones. The dominance of residue 71 was also observed with an influenza hemagglutinin-specific HLA-DR BON-restricted T cell line.

Amino Acid Sequence↗

PubMed1994

Common and divergent peptide binding specificities of hsp70 molecular chaperones.

We have studied the binding of synthetic peptides to three hsp70 molecular chaperones, DnaK, BiP, and hsc70, as a model for the interaction of hsp70 proteins with unfolded regions of target polypeptides. We measured the ability of 53 peptides to inhibit the formation of complexes between the hsp70 proteins and denatured lactalbumin. Peptides that bound with highest affinity to all three hsp70 proteins contained stretches of at least 7 residues that included large hydrophobic and basic amino acids, but few or no acidic residues. Amino acid substitutions within one heptameric peptide showed that an important feature for its binding to all three chaperones was a large hydrophobic residue in position 4, while specificity differences between the chaperones were revealed by substitutions at positions 2 and 6. Such specificity differences were frequently observed with other peptides, the most extreme example being a peptide rich in basic residues that bound with high affinity to DnaK, intermediate affinity to hsc70, and negligible affinity to BiP. Substitution of a lysine residue at position 2 in this peptide by tyrosine abolished the specificity difference by increasing the affinities of the DnaK and hsc70 proteins 5- and 20-fold, respectively, and that of BiP by greater than 2 orders of magnitude. Thus, hsp70 proteins can exhibit common or exclusive binding specificities, depending on the peptide sequence.

Adenosine Triphosphatases↗

PubMed2006

Prion-derived copper-binding peptide fragments catalyze the generation of superoxide anion in the presence of aromatic monoamines.

OBJECTIVES: Studies have proposed two opposing roles for copper-bound forms of prion protein (PrP) as an anti-oxidant supporting the neuronal functions and as a pro-oxidant leading to neurodegenerative process involving the generation of reactive oxygen species. The aim of this study is to test the hypothesis in which putative copper-binding peptides derived from PrP function as possible catalysts for monoamine-dependent conversion of hydrogen peroxide to superoxide in vitro. MATERIALS AND METHODS: Four peptides corresponding to the copper (II)-binding motifs in PrP were synthesized and used for analysis of peptide-catalyzed generation of superoxide in the presence of Cu (II) and other factors naturally present in the neuronal tissues. RESULTS: Among the Cu-binding peptides tested, the amino acid sequence corresponding to the Cu-binding site in the helical region was shown to be the most active for superoxide generation in the presence of Cu(II), hydrogen peroxide and aromatic monoamines, known precursors or intermediates of neurotransmitters. Among monoamines tested, three compounds namely phenylethylamine, tyramine and benzylamine were shown to be good substrates for superoxide-generating reactions by the Cu-bound helical peptide. CONCLUSIONS: Possible roles for these reactions in development of prion disease were suggested.

Amines↗

PubMed2000

Multi-center clinical comparison of combination anorganic bovine-derived hydroxyapatite matrix (ABM)/cell binding peptide (P-15) and ABM in human periodontal osseous defects. 6-month results.

BACKGROUND: Intraosseous periodontal defects present a particular treatment problem. New bone replacement grafts offer promise for improved results. METHODS: The role of a synthetic cell-binding peptide (P-15), combined with anorganic [corrected] bovine-derived hydroxyapatite bone matrix (ABM), was compared to ABM alone in human periodontal osseous defects in a controlled, monitored, multi-center trial. Following appropriate initial preparation procedures, flap surgery with defect and root debridement was performed. Two osseous defects per patient were treated randomly with each procedure after surgical preparation. Appropriate periodontal maintenance schedules were followed, and at 6 to 7 months, re-entry flap surgery was performed for documentation and finalization of treatment. RESULTS: T test and Mann-Whitney U analyses of patient mean values from 33 patients revealed that the combination ABM/P-15 grafts demonstrated significantly better mean defect fill of 2.9 +/- 1.2 mm (72.9%) versus a mean defect fill of 2.2 +/- 1.4 mm (50.67%) for defects treated with ABM (P<0.05). Other hard tissue findings showed similar clinically superior results with the use of ABM/P-15. Relative defect fill results showed 81% positive (50% to 100% defect fill) responses with ABM/P-15 and 67% positive responses with ABM. There were 3.5 times as many optimal results (> or = 90% defect fill) with ABM/P-15 and twice as many failures (minimal response) with ABM. Soft tissue findings showed no significant differences between treatments. CONCLUSIONS: These results suggest that the use of the P-15 synthetic cell-binding peptide combined with ABM yields better clinical results than the ABM alone in intrabony periodontal defects.

Adult↗

PubMed1994

A peptide binding weakly to the major histocompatibility molecule augments T cell responses.

An I-A(d)-derived peptide PB1 was found to enhance the reactivity of I-A(d)-restricted T cells. The augmentative effect was not due to the cross-reactivity of PB1 peptide with antigens. PB1 had no effect on T cells specific for I-A(b) and I-E(k), nor did PB1 increase the T cell responses to concanavalin A and staphylococcal enterotoxin B. The strict I-A(d) specificity suggests that PB1 enhances the recognition of antigen-I-A(d) complex by T cell receptor. PB1 bound to I-A(d) weakly. The augmentative effect could be found on other I-A(d)-binding peptides in appropriate conditions; however, PB1 was distinct in its prominently augmentative effect on all the I-A(d)-restricted T cells analyzed. A similar enhancing activity was demonstrated on a synthetic transferrin receptor peptide with minimum affinity for I-A(d). The unusual enhancing activity of PB1 may thus be attributed to the low I-A(d) binding affinity. It was postulated that the binding of low-affinity PB1 would not only stabilize I-A(d) structure, but also enhance the binding of other peptides. This was supported by the increased binding of OVA 323-339 and cI 84-98 to I-A(d) in the presence of PB1. The inclusion of PB1 in the immunization mixture also enhanced T cell responses in vivo, suggesting the possibility of using low-affinity peptide to promote specific immunity.

Amino Acid Sequence↗

PubMed2004

Antimicrobial activities of heparin-binding peptides.

Antimicrobial peptides are effector molecules of the innate immune system. We recently showed that the human antimicrobial peptides alpha-defensin and LL-37 bind to glycosaminoglycans (heparin and dermatan sulphate). Here we demonstrate the obverse, i.e. structural motifs associated with heparin affinity (cationicity, amphipaticity, and consensus regions) may confer antimicrobial properties to a given peptide. Thus, heparin-binding peptides derived from laminin isoforms, von Willebrand factor, vitronectin, protein C inhibitor, and fibronectin, exerted antimicrobial activities against Gram-positive and Gram-negative bacteria. Similar results were obtained using heparin-binding peptides derived from complement factor C3 as well as consensus sequences for heparin-binding (Cardin and Weintraub motifs). These sequence motifs, and additional peptides, also killed the fungus Candida albicans. These data will have implications for the search for novel antimicrobial peptides and utilization of heparin-protein interactions should be helpful in the identification and purification of novel antimicrobial peptides from complex biological mixtures. Finally, consensus regions may serve as templates for de novo synthesis of novel antimicrobial molecules.

Amino Acid Motifs↗

PubMed1997

A peptide-binding motif for I-A(g7), the class II major histocompatibility complex (MHC) molecule of NOD and Biozzi AB/H mice.

The class II major histocompatibility complex molecule I-A(g7) is strongly linked to the development of spontaneous insulin-dependent diabetes mellitus (IDDM) in non obese diabetic mice and to the induction of experimental allergic encephalomyelitis in Biozzi AB/H mice. Structurally, it resembles the HLA-DQ molecules associated with human IDDM, in having a non-Asp residue at position 57 in its beta chain. To identify the requirements for peptide binding to I-A(g7) and thereby potentially pathogenic T cell epitopes, we analyzed a known I-A(g7)-restricted T cell epitope, hen egg white lysozyme (HEL) amino acids 9-27. NH2- and COOH-terminal truncations demonstrated that the minimal epitope for activation of the T cell hybridoma 2D12.1 was M12-R21 and the minimum sequence for direct binding to purified I-A(g7) M12-Y20/K13-R21. Alanine (A) scanning revealed two primary anchors for binding at relative positions (p) 6 (L) and 9 (Y) in the HEL epitope. The critical role of both anchors was demonstrated by incorporating L and Y in poly(A) backbones at the same relative positions as in the HEL epitope. Well-tolerated, weakly tolerated, and nontolerated residues were identified by analyzing the binding of peptides containing multiple substitutions at individual positions. Optimally, p6 was a large, hydrophobic residue (L, I, V, M), whereas p9 was aromatic and hydrophobic (Y or F) or positively charged (K, R). Specific residues were not tolerated at these and some other positions. A motif for binding to I-A(g7) deduced from analysis of the model HEL epitope was present in 27/30 (90%) of peptides reported to be I-A(g7)-restricted T cell epitopes or eluted from I-A(g7). Scanning a set of overlapping peptides encompassing human proinsulin revealed the motif in 6/6 good binders (sensitivity = 100%) and 4/13 weak or non-binders (specificity = 70%). This motif should facilitate identification of autoantigenic epitopes relevant to the pathogenesis and immunotherapy of IDDM.

Amino Acid Sequence↗

PubMed2003

Role of the interdomain linker probed by kinetics of CO ligation to an endothelial nitric oxide synthase mutant lacking the calmodulin binding peptide (residues 503-517 in bovine).

Oxygenase and reductase domains in nitric oxide synthase are linked by a peptide region that binds calmodulin. Here we study the effects of modifying the length of the interdomain linker in a deletion mutant lacking 15 amino acids (residues 503-517) in bovine eNOS. The kinetics of CO ligation with the mutant were determined in the presence and absence of tetrahydrobiopterin and arginine and compared with the CO binding kinetics of wild-type eNOS and the eNOS oxygenase domain. In the mutant, electron flow is interrupted. The association kinetics of CO with both mutant and wild-type eNOS can be approximated with two kinetic phases, but the relative proportions change in the mutant. Both the abrogation of electron flow in the mutant and the differences in CO binding may be explained by an alteration in the docking of the FMN domain to the heme domain. We propose that the calmodulin binding residues form a helix that is critical for the proper alignment of the adjacent reductase and oxygenase domains within the active eNOS dimer in achieving proper electron transfer between them.

Amino Acid Sequence↗

PubMed1991

Direct analysis of peptide binding to cell-associated MHC class I molecules.

Exogenously added synthetic peptides can mimic endogenously produced antigenic peptides recognized on target cells by MHC class I-restricted cytolytic T lymphocytes. While it is assumed that exogenous peptides associate with class I molecules on the target cell surface, direct binding of peptides to cell-associated class I molecules has been difficult to demonstrate. Using a newly developed binding assay based on photoaffinity labeling, we have investigated the interaction of two antigenic peptides, known to be recognized in the context of H-2Kd or H-2Db, respectively, with 20 distinct class I alleles on living cells. None of the class I alleles tested, with the exception of H-2Kd or H-2Db, bound either of the peptides, thus demonstrating the exquisite specificity of peptide binding to class I molecules. Moreover, peptide binding to cell-associated H-2Kd was drastically reduced when metabolic energy, de novo protein synthesis or protein egress from the endoplasmic reticulum was inhibited. It is thus likely that exogenously added peptides do not associate with the bulk of class I molecules expressed at the cell surface, but rather bind to short-lived molecules devoid of endogenous peptides.

Adenovirus Early Proteins↗

PubMed2003

Selection of chronic lymphocytic leukemia binding peptides.

To provide cell-binding ligands for ex vivo gene therapy and chronic lymphocytic leukemia (CLL)-targeting ligands for in vivo drug and gene therapy, we selected 44 20-mer peptides from peptide-presenting phage libraries by panning against primary patient CLL cancer cells. Twenty-nine of the selected peptides were assayed for cell binding. Eight of the selected peptides bound CLL cells, B cells, T cells, and monocyte cells, 12 bound only CLL cells and B cells, and 1 peptide bound only B cells. However, eight of the selected peptides were CLL specific. When two of the peptides were tested out of the context of phage, the synthetic peptides were able to bind cells and functionally retarget adenovirus to increase ex vivo gene delivery to primary CLL cells. These data demonstrate the ability to identify lead cancer-targeting peptides by selection of phage libraries against primary human cancers cells.

Adenoviridae↗

PubMed1983

Occurrence of acid-labile sulfide in cadmium-binding peptide 1 from fission yeast.

Two kinds of Cd-binding peptides (Cd-BP1 and Cd-BP2) are induced in fission yeast upon addition of CdCl2 to the culture medium (l). It was also reported that Cd-BP1 and Cd-BP2 consisted of the same components, unit peptides (Cys3, Glu3, Gly1) and Cd atoms, though the respective amounts of components in each molecule were different (1, 2). Now, we have found that Cd-BP1 contains about 1 mol of acid-labile sulfide per mol, and Cd-BP2 contains no labile sulfide. The existence of the labile sulfide explains the unique physicochemical characteristics of Cd-BP1. Since acid-labile sulfide has not been found in metallothioneins or other metallothionein-like metal-binding proteins, the occurrence of labile sulfide in Cd-BP1 is the first instance in this field.

Ascomycota↗

PubMed1999

The lack of consensus for I-A(g7)-peptide binding motifs: is there a requirement for anchor amino acid side chains?

We discuss here the problems in identifying sequence motifs of peptides that bind to I-A(g7), the class II histocompatibility molecule of NOD diabetic mice. We present studies that indicate a minor contribution of amino acid side chains for binding. A peptide from the Ealpha chain binds to I-A(g7) molecules and is recognized by CD4 T cells. By producing single-residue mutations we identified four residues that were considered to contact the T cell receptor. No residue was found to be essential for binding to I-A(g7): a peptide that contained the T cell contact residues, on a backbone of alanines, bound to I-A(g7) and stimulated the T cells. We conclude that peptides can bind to I-A(g7) without the requirement for residues with prominent side chains to anchor them.

Animals↗

PubMed2004

Comparison of cell viability on anorganic bone matrix with or without P-15 cell binding peptide.

Cell-extracellular cell matrix (ECM) interactions play a vital role in development including cytoskeletal structure, growth and differentiation. A 15 amino acid, non-RGD containing, peptide that is derived from type I collagen was tested for its ability to confer cell survival. Two routinely utilized bone graft materials, anorganic bone matrix (ABM) and ABM carrying the cell binding peptide P-15 were compared for cell viability and apoptosis. Anchorage-dependent human foreskin fibroblasts (HFF) or osteogenic MC3T3-E1 cells were seeded on ABM or ABM/P-15. After serum withdrawal, viability and level of apoptosis were significantly (p<0.05) improved for cells on ABM/P-15 compared to cells on ABM. Scanning electron microscopy confirmed large, spread cells on ABM/P-15 and smaller cells with apoptotic cellular blebs on ABM. In addition, viable cell attachment was significantly greater on cells cultured on ABM/P-15 compared with demineralized freeze-dried bone allograft. This is the first report that the P-15 cell binding peptide, when complexed with ABM, promotes cell survival. The P-15 peptide may modulate cell number and tissue structure by the enhancement of viable cell attachment and via the regulation of apoptosis.

3T3 Cells↗