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Biomedical subjects

B A Jameson

Publications and source records attributed to B A Jameson.

At least 19 recordsLinked to original sources
PubMed1992

Inhibition of cellular proliferation by peptide analogues of insulin-like growth factor 1.

The activation of the insulin-like growth factor 1 (IGF-1) receptor by its ligand plays a central role in the growth of most cell types. We have used the techniques of computational chemistry in order to design and synthesize several novel analogues of IGF-1. These analogues were able to inhibit the autophosphorylation of the IGF-1 receptor as well as the growth of several different cell types, including prostate carcinoma cells and SV40-transformed cells. Additionally, we have found that D-amino acid analogues of these peptides are apparently resistant to the proteolytic degradation that occurs in the presence of whole sera. Consequently, these analogues seem to show great potential both as probes of the structure/function activities of the IGF-1 signalling pathway and as novel clinical strategies in controlling abnormal cellular growth.

3T3 Cells↗
PubMed1992

Direct involvement of the CDR3-like domain of CD4 in T helper cell activation.

The CD4 glycoprotein, a member of the Ig super-family, has long been known to play an important role in the immunologic activation of Th cells. The precise manner in which CD4 participates in this activation process is not yet understood. In an attempt to further define its role in Th cell activation, we modeled the D1 domain of the murine CD4 protein (L3T4) based on the experimentally determined high resolution structure of the human CD4 protein. Because the D1 domain of CD4 strongly resembles the V kappa chain of an antibody, we addressed the question of whether the CDR-like regions of CD4 are also involved in mediating protein-protein interactions. Consequently, we used the modeled L3T4 structure as a template in the design of conformational mimics of the CDR3-like region (residues 86-94). Only the analog designed to mimic both the sequence and conformation of this region exhibited highly specific inhibition of CD4-dependent responses. Because the inhibitory activity could be localized to the Th cell itself, it appears that this analog acts by uncoupling a CD4 association (independent of an APC) critical to generating a proliferative response.

Amino Acid Sequence↗
PubMed1992

Fine mapping of the high molecular weight kininogen binding site on blood coagulation factor XI through the use of rationally designed synthetic analogs.

Using immunological and chemical cleavage techniques, we have previously identified a domain contained within residues Phe56-Ser86 in the first tandem repeat (A1) of the heavy chain of factor XI which binds high Mr kininogen (Baglia, F. A., Jameson, B. A., and Walsh, P. N. (1990) J. Biol. Chem. 265, 4149-4154). We have now chemically synthesized peptides from corresponding homologous regions in the second (A2), third (A3), and fourth (A4) tandem repeats of the heavy chain (A2: Asn145-Ala176; A3: Asn235-Arg266; and A4: Gly326-Lys357). These peptides had no effect on the binding of factor XI to high Mr kininogen. Because of a lack of detailed structural information for the A1 domain, a molecular model of this region was constructed. This hypothetical model made distinct and testable predictions regarding potential surfaces and concomitant secondary structure. Specifically, the resulting structure depicted two juxtaposed beta-stranded stem-loops that, in conjunction with biological information, constitute a candidate surface for contact with high Mr kininogen. The hypothetical A1 model was, consequently, used as a predictive template in the rational design of two synthetic peptides (Val59-Arg70 and Asn72-Lys83). When both these peptides were added together and the binding of factor XI to high Mr kininogen was examined, a synergistic inhibitory effect was observed compared with each peptide added individually. Our data are consistent with the notion that the sequence of amino acids from Val59-Lys83 of the heavy chain of factor XI contains two antiparallel beta-strands connected by beta-turns that together comprise a continuous surface utilized for the binding of high Mr kininogen.

Amino Acid Sequence↗
PubMed1992

Conserved structural features in the interaction between retroviral surface and transmembrane glycoproteins?

Among the retroviruses, the surface (SU) and transmembrane (TM) glycoproteins of lentiviruses are linked exclusively by noncovalent bonds. For some C-type retroviruses, however, a small proportion of the SU proteins has been shown to be linked to their TM proteins by a disulfide bond, with the remainder being noncovalently associated. A region near the carboxyl terminus of the HIV-1 SU glycoprotein has been implicated in contacting the TM glycoprotein. Computer modelling indicates that this region of divergent lentivirus and oncovirus SU glycoproteins forms a structurally conserved "pocket" which could accommodate a "knob"-like protrusion formed by an immunodominant region in the TM protein containing the CxxxxxC (lentiviruses) or CxxxxxxCC (C- and D-type viruses) motif. An anti-idiotypic monoclonal antibody, raised against a monoclonal antibody reacting with a sequence in the "pocket" of HIV-1 gp120, was found to bind to synthetic peptides close to the CxxxxxC motif. It is suggested that part of the SU-TM linkage mechanism for the lentiviruses and oncoviruses is a 'knob and socket' structure and that the interaction between SU and TM proteins is similar in one region for lentiviruses and C-type as well as D-type viruses. The conserved knob and socket linkage may be relevant to a mechanism for viral-cell membrane fusion that is broadly common to all of these retroviruses.

Amino Acid Sequence↗
PubMed1991

Identification and chemical synthesis of a substrate-binding site for factor IX on coagulation factor XIa.

We have previously used monoclonal antibodies to identify an epitope on the heavy chain of factor XIa that is a substrate-binding site for factor IX (Sinha, D., Seaman, F.S., and Walsh, P.N. (1987) Biochemistry 26, 3768-3775; Baglia, F.A., Sinha, D., and Walsh, P.N. (1989) Blood 74, 244-251). To define the factor XIa domain that binds factor IX, we have now screened a panel of factor XI heavy chain-derived synthetic peptides for their capacity to inhibit the formation of an activation peptide reflecting factor IX activation by factor XIa. Peptide Asn145-Ala176 (which is located in the second tandem repeat or A2 domain of the factor XI heavy chain) is a competitive inhibitor of factor IX activation by factor XIa with a Ki of 30 nM, whereas structurally similar peptides in the A1, A3, and A4 domains were required at 10-1000-fold higher concentrations for similar effects, and a synthetic peptide identical with a highly homologous region of the heavy chain A2 domain of prekallikrein (Tyr143-Ala176) had no effect on factor IX activation by factor XIa. Because detailed structural information is lacking, a potential three-dimensional structure for the factor XI A2 domain was calculated based on its sequence information in conjunction with previously determined structural constraints. The resulting structure depicted three juxtaposed beta-stranded stem-loops that, based on biological information, constitute a candidate surface for contact with factor IX. The A2 model was therefore used as a template in the rational design of three synthetic peptides (Ala134-Ile146 (peptide a), Leu148-Arg159 (peptide b), and Ile160-Leu172 (peptide c]. When peptides a and b or a and c were added together and the activation of factor IX by factor XIa was examined, a synergistic inhibitory effect was observed, compared with each peptide added individually, whereas peptides b and c showed additive effects. Our data suggest that the sequence of amino acids from Ala134 through Leu172 of the heavy chain of factor XI contains three antiparallel beta-strands connected by beta-turns that together comprise a continuous surface utilized for the binding of factor IX.

Amino Acid Sequence↗
PubMed1991

Identification of the disulfide bond pattern in albolabrin, an RGD-containing peptide from the venom of Trimeresurus albolabris: significance for the expression of platelet aggregation inhibitory activity.

Albolabrin is a 73 amino acid peptide isolated from the venom of Trimeresurus albolabris. It contains an RGD sequence and 12 cysteines and is a potent inhibitor of both platelet aggregation and fibrinogen binding to the GPIIb/IIIa complex. This protein shows a high degree of analogy (primarily due to the alignment of all cysteines and the RGD) with a number of other viper venom proteins which inhibit cell adhesion and platelet aggregation and are referred to as disintegrins: rhodostomin, trigramin, flavoridin, applagin, elegantin, and batroxostatin. In this study, we found that the reduction and vinylpyridylethylation of albolabrin and flavoridin decreased their platelet aggregation inhibitory activity approximately 40-50 times. It can be postulated that the higher potency of native and reduced flavoridin as compared to albolabrin depends on the substitution of the Asp of albolabrin with a Phe at the C-terminal end of the RGD in flavoridin. The activity of a synthetic C-terminal peptide derived from flavoridin (residues 35-65) containing four cysteines was about 75 times lower than that of the original flavoridin. The substitution of a pair of cysteine residues with alanines in this peptide resulted in further loss of activity. In order to identify the disulfide bonds in albolabrin, the molecule was digested consecutively by trypsin and porcine pancreatic elastase. Peptides resulting from this digestion were isolated by reverse-phase HPLC and identified by amino acid composition and mass spectrometry.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1990

Localization of the high molecular weight kininogen binding site in the heavy chain of human factor XI to amino acids phenylalanine 56 through serine 86.

We have previously demonstrated that a monoclonal antibody (5F7) directed against the heavy chain region of factor XI inhibits the binding of factor XI to high molecular weight kininogen (high Mr kininogen) and the surface-mediated proteolytic activation of factor XI by factor XIIa in the presence of high Mr kininogen. In order to identify the structural domain of factor XI that binds high Mr kininogen, CNBr-digested factor XI was passed over a 5F7 antibody affinity column. One of two CNBr peptides that bound to this 5F7 affinity column inhibited binding of 125I-factor XI to high Mr kininogen, as did intact factor XI. Polyacrylamide gel electrophoresis in sodium dodecyl sulfate of an inhibitory peptide purified by high performance liquid chromatography revealed an Mr of 10,000-15,000. Gas-phase sequencing of this peptide revealed the following amino-terminal sequence: X-X-Val-Thr-Gln-Leu-Leu-Lys-Asp-Thr. These data together with the amino acid composition of the isolated peptide indicate that both the epitope recognized by antibody 5F7 and at least a portion of the high Mr kininogen binding site are contained within the amino-terminal portion of factor XI comprising residues Glu-1 through Met-102. Further cleavage of this peptide with o-iodosobenzoic acid at a tryptophanyl peptide bond revealed that an Mr 5,000 peptide (with the amino-terminal sequence Trp-Phe-Thr-Cys-Val-Leu) bound to a high Mr kininogen affinity column and inhibited binding of 125I-factor XI to high Mr kininogen. Finally, a synthetic peptide comprising residues Phe-56 through Ser-86 inhibited 125I-factor XI binding to high Mr kininogen. These experiments strongly suggest that the high Mr kininogen binding site is contained within the domain in the heavy chain region of factor XI comprising residues Phe-56 through Ser-86.

Amino Acid Sequence↗
PubMed1988

Location and chemical synthesis of a binding site for HIV-1 on the CD4 protein.

The human immunodeficiency virus type 1 (HIV-1) uses the CD4 protein as a receptor for infection of susceptible cells. A candidate structure for the HIV-1 binding site on the CD4 protein was identified by epitope mapping with a family of eight functionally distinct CD4-specific monoclonal antibodies in conjunction with a panel of large CD4-derived synthetic peptides. All of the seven epitopes that were located reside within two immunoglobulin-like disulfide loops situated between residues 1 and 168 of the CD4 protein. The CD4-specific monoclonal antibody OKT4A, a potent inhibitor of HIV-1 binding, recognized a site between residues 32 and 47 on the CD4 protein. By analogy to other members of the immunoglobulin superfamily of proteins, this particular region has been predicted to exist as a protruding loop. A synthetic analog of this loop (residues 25 to 58) showed a concentration-dependent inhibition of HIV-1-induced cell fusion. It is proposed that a loop extending from residues 37 to 53 of the CD4 protein is a binding site for the AIDS virus.

Antibodies, Monoclonal↗
PubMed1988

The antigenic index: a novel algorithm for predicting antigenic determinants.

In this paper, we introduce a computer algorithm which can be used to predict the topological features of a protein directly from its primary amino acid sequence. The computer program generates values for surface accessibility parameters and combines these values with those obtained for regional backbone flexibility and predicted secondary structure. The output of this algorithm, the antigenic index, is used to create a linear surface contour profile of the protein. Because most, if not all, antigenic sites are located within surface exposed regions of a protein, the program offers a reliable means of predicting potential antigenic determinants. We have tested the ability of this program to generate accurate surface contour profiles and predict antigenic sites from the linear amino acid sequences of well-characterized proteins and found a strong correlation between the predictions of the antigenic index and known structural and biological data.

Algorithms↗
PubMed1988

An integrated family of amino acid sequence analysis programs.

During the last years abundant sequence data has become available due to the rapid progress in protein and DNA sequencing techniques. The exact three-dimensional structures, however, are available only for a fraction of proteins with known sequences. For many purposes the primary amino acid sequence of a protein can be directly used to predict important structural parameters. However, mathematical presentation of the calculated values often makes interpretation difficult, especially if many proteins must be analysed and compared. Here we introduce a broad-based, user-defined analysis of amino acid sequence information. The program package is based on published algorithms and is designed to access standard protein data bases, calculate hydropathy, surface probability and flexibility values and perform secondary structure predictions. The data output is in an 'easy-to-read' graphic format and several parameters can be superimposed within a single plot in order to simplify data interpretations. Additionally, this package includes a novel algorithm for the prediction of potential antigenic sites. Thus the software package presented here offers a powerful means of analysing an amino acid sequence for the purpose of structure/function studies as well as antigenic site analyses. These algorithms were written to function in context with the UWGCG (University of Wisconsin Genetics Computer Group) program collection, and are now distributed within that package.

Algorithms↗
PubMed1988

Identification of a novel retroviral gene unique to human immunodeficiency virus type 2 and simian immunodeficiency virus SIVMAC.

Human and simian immunodeficiency-associated retroviruses are extraordinarily complex, containing at least five genes, tat, art, sor, R, and 3' orf, in addition to the structural genes gag, pol, and env. Recently, nucleotide sequence analysis of human immunodeficiency virus type 2 (HIV-2) and simian immunodeficiency virus SIVMAC revealed the existence of still another open reading frame, termed X, which is highly conserved between these two viruses but absent from HIV-1. In this report, we demonstrate for the first time that the X open reading frame represents a functional retroviral gene in both HIV-2 and SIVMAC and that it encodes a virion-associated protein of 14 and 12 kilodaltons, respectively. We also describe the production of recombinant TrpE/X fusion proteins in Escherichia coli and show that sera from some HIV-2-infected individuals specifically recognize these proteins.

Amino Acid Sequence↗
PubMed1987

Hepatitis B virus proteins eliciting protective immunity.

The immune response to current hepatitis B vaccines appears to be qualitatively different from the response elicited during recovery from natural infection. Such disparate responses can probably be explained by the absence or under-representation of preS- and the nucleoprotein core-specific determinants in the vaccines. The incorporation of these determinants into future vaccines may improve their efficacy.

Hepatitis B↗
PubMed1985

Antigenic variation and resistance to neutralization in poliovirus type 1.

Mutations have been identified in variants of poliovirus, type 1 (Mahoney) on the basis of their resistance to neutralization by individual monoclonal antibodies. The phenotypes of these variants were defined in terms of antibody binding; the pattern of epitopes expressed or able to be exploited for neutralization were complex. Single amino acid changes can have distant (in terms of linear sequence) and generalized effects on the antigenic structure of poliovirus and similarly constituted virions.

Amino Acid Sequence↗
PubMed1985

Natural variants of the Sabin type 1 vaccine strain of poliovirus and correlation with a poliovirus neutralization site.

Independent substitution mutations have been detected in capsid polypeptide VP1 of the type 1 oral poliovirus vaccine isolated from normal infant vaccine recipients. These mutations map at amino acid residues 142 and 147 of VP1, a region only minimally hydrophilic. A synthetic peptide, corresponding to residues 141 to 147 of VP1 was synthesized, conjugated to a carrier polypeptide of bovine serum albumin. The conjugate was found to elicit a weak poliovirus neutralizing antibody response. It was also capable of priming the immune system for the production of IgG-type antibodies able to neutralize greater than 99.999% of infectious type 1 virus. It is suggested that region 141 to 147 of VP1 may be involved in neutralization of the virus and that the mutants may have accumulated by antibody selection.

Antigen-Antibody Complex↗
PubMed1985

The immune response to poliovirus-specific synthetic peptides: effects of adjuvants and test animal species.

Carrier protein conjugates of five synthetic peptides containing amino acid sequences specific to capsid proteins VP1 and VP2 of poliovirus type 1 were tested for their abilities to elicit an immune response in the presence of either of two adjuvants and in several animal species. Freund's adjuvant induced significantly higher level anti-peptide antibody titers than A1(OH)3. However, no difference was noted between the two adjuvants in their abilities to aid in the induction of cross-reactive virus neutralizing antibody. The latter antibody was more readily produced by rabbits than by guinea pigs in spite of equivalent anti-peptide titers. Rats failed to produce neutralizing antibodies and their anti-peptide antibody levels were generally lower. The significance of these results for studies involving the development of synthetic peptide immunogens is discussed.

Adjuvants, Immunologic↗
PubMed1984

Identification of a new neutralization antigenic site on poliovirus coat protein VP2.

Major neutralization antigenic sites have been previously mapped by us on VP1, the largest capsid protein of poliovirus type 1. Here we report the first identification of the primary sequence of a neutralization antigenic site on capsid protein VP2. Inspection of the amino acid sequence of VP2 led to the selection and synthesis of a peptide (n = 12) that, after linking to a carrier protein, induced an antiviral neutralizing antibody response in rabbits. The response was augmented by a single subsequent inoculation of intact virus; thus, the peptide was also capable of priming the production of neutralizing antibodies. These antibodies were directed only against the site specified by the synthetic peptide. Although the VP2-specific neutralization antigenic site appears not to be strongly immunogenic in the intact virion, it can nevertheless contribute to neutralization of poliovirus. This observation may be important for the development of peptide vaccines.

Amino Acid Sequence↗