Deamidation of soluble CD4 at asparagine-52 results in reduced binding capacity for the HIV-1 envelope glycoprotein gp120

Teshima, Glen; Porter, J G; Yim, Kalvin; Ling, Victor; Guzzetta, Andrew W.

doi:10.1021/bi00230a016

Cited by 50 publications

(28 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A follow-on study that defines the identity and extent of post-translational modifications for amino acids in rPA by LC/MS/MS will be described separately (Powell et al, in preparation). A reduction or complete loss of in vitro or in vivo biological activities has been reported for a variety of deamidated proteins [27,28], while others appear unaffected [29]. It is therefore important to establish methods for evaluating the effects of deamidation on the biological activities and antigenicities of vaccine candidate polypeptides.…”

Section: Discussionmentioning

confidence: 99%

Comparative vaccine efficacy of different isoforms of recombinant protective antigen against Bacillus anthracis spore challenge in rabbits

Ribot

Powell

Ivins

et al. 2006

Vaccine

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Comparative vaccine efficacy of different isoforms of recombinant protective antigen against Bacillus anthracis spore challenge in rabbits

Ribot

Powell

Ivins

et al. 2006

Vaccine

View full text Add to dashboard Cite

“…At higher levels of AEP, additional Asn residues in TTCF are targeted. 2 Peptides generated from cleavage by AEP at these minor sites were more prevalent in a digest of TTCF37, providing further evidence that aging TTCF perturbed the normal pattern of proteolytic degradation.…”

Section: Resultsmentioning

confidence: 90%

“…For example, a recent study demonstrated that the DNA-damaging antineoplastic drug cisplatin induced the deamidation of two asparagine residues in a flexible loop of the antiapoptotic protein Bcl-xL, preventing its interaction with other proapoptotic Bcl family members and thereby inducing apoptosis (1). Other studies document the deleterious effects of asparagine deamidation on the CD4 binding activity of human immunodeficiency virus gp120 (2), the co-mitogenic and receptor binding activity of murine IL1-␤ 1 (3), and the angiogenic activity of angiogenin (4). Immune recognition of proteins and peptides can also be affected by deamidation/isomerization of asparagine and glutamine residues.…”

mentioning

confidence: 99%

Asparagine Deamidation Perturbs Antigen Presentation on Class II Major Histocompatibility Complex Molecules

Moss

Matthews

Lamont

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Post-translational protein modifications can be recognized by B and T lymphocytes and can potentially make "self"-proteins appear foreign to the immune system. Such modifications may directly affect major histocompatibility complex-restricted T cell recognition of processed peptides or may perturb the processing events that generate such peptides. Using the tetanus toxin C fragment protein as a test case, we show that spontaneous deamidation of asparagine residues interferes with processing by the enzyme asparagine endopeptidase (AEP) and contributes to diminished antigen presentation. Deamidation inhibits AEP action either directly, when asparagine residues targeted by AEP are modified, or indirectly, when adjacent Asn residues are deamidated. Thus, deamidation of long-lived self-proteins may qualitatively or quantitatively affect the spectrum of self-peptides displayed to T cells and may thereby contribute to the onset or exacerbation of autoimmune disease.Asparagine deamidation is the most common spontaneous post-translational protein modification and is increasingly recognized as having an important impact on protein function. For example, a recent study demonstrated that the DNA-damaging antineoplastic drug cisplatin induced the deamidation of two asparagine residues in a flexible loop of the antiapoptotic protein Bcl-xL, preventing its interaction with other proapoptotic Bcl family members and thereby inducing apoptosis (1). Other studies document the deleterious effects of asparagine deamidation on the CD4 binding activity of human immunodeficiency virus gp120 (2), the co-mitogenic and receptor binding activity of murine IL1-␤ 1 (3), and the angiogenic activity of angiogenin (4). Immune recognition of proteins and peptides can also be affected by deamidation/isomerization of asparagine and glutamine residues. For example, T cells have been described that specifically recognize peptides containing asparagine residues that have either cyclized (5) or become deamidated to aspartic acid (6, 7). As has been pointed out (8), the appearance of such modifications in "self"-proteins may disturb the delicate balance that the immune system establishes between tolerance to self-proteins on the one hand but an ability to respond to foreign entities on the other. For example, mice showed no response to unmodified forms of a self-cytochrome c peptide (90 -104) or to a small nuclear ribonucleoprotein D peptide (65-79) but developed strong T and B cell responses to forms of these peptides in which a single Asp residue had been modified to iso-Asp (9). Importantly, the B cell response to the iso-Asp containing peptide cross-reacted with the native protein, suggesting a plausible chain of events initiated by post-translational protein modification that may lead to autoreactivity. In the case of ␣-gliadin, a single glutamine residue, likely deamidated as a result of tissue transglutaminase action, is found in two overlapping T cell epitopes recognized by T cells from human leukocyte antigen-DQ2-positive celiac disease patien...

show abstract

“…Isoaspartyl (iso-Asp) 3 post-translational protein modification occurs at physiological temperatures and pH values (1), and a wide variety of intracellular and extracellular proteins has been identified with iso-Asp modifications. Iso-Asp formation is prevalent in stressed (heat shock) or aged cells (2), and the presence of iso-Asp residues in proteins has been shown to decrease biological functions in some proteins (3).…”

Section: T Cells Not Only Recognized the Isoaspartyl Trp-2 Peptide Bumentioning

confidence: 99%

“…Iso-Asp formation is prevalent in stressed (heat shock) or aged cells (2), and the presence of iso-Asp residues in proteins has been shown to decrease biological functions in some proteins (3). Iso-Asp residues can be repaired by the ubiquitous enzyme protein carboxyl methyltransferase (4).…”

Section: T Cells Not Only Recognized the Isoaspartyl Trp-2 Peptide Bumentioning

confidence: 99%

Isoaspartyl Post-translational Modification Triggers Anti-tumor T and B Lymphocyte Immunity

Doyle

Zhou

Wolff

et al. 2006

Journal of Biological Chemistry

View full text Add to dashboard Cite

A hallmark of the immune system is the ability to ignore selfantigens. In attempts to bypass normal immune tolerance, a post-translational protein modification was introduced into self-antigens to break T and B cell tolerance. We demonstrate that immune tolerance is bypassed by immunization with a post-translationally modified melanoma antigen. In particular, the conversion of an aspartic acid to an isoaspartic acid within the melanoma antigen tyrosinase-related protein (TRP)-2 peptide-(181-188) makes the otherwise immunologically ignored TRP-2 antigen immunogenic. Tetramer analysis of isoAsp TRP-2 peptide-immunized mice demonstrated that CD8 ؉ T cells not only recognized the isoaspartyl TRP-2 peptide but also the native TRP-2 peptide. These CD8 ؉ T cells functioned as cytotoxic T lymphocytes, as they effectively lysed TRP-2 peptide-pulsed targets both in vitro and in vivo. Potentially, posttranslational protein modification can be utilized to trigger strong immune responses to either tumor proteins or potentially weakly immunogenic pathogens. Isoaspartyl (iso-Asp)3 post-translational protein modification occurs at physiological temperatures and pH values (1), and a wide variety of intracellular and extracellular proteins has been identified with iso-Asp modifications. Iso-Asp formation is prevalent in stressed (heat shock) or aged cells (2), and the presence of iso-Asp residues in proteins has been shown to decrease biological functions in some proteins (3). Iso-Asp residues can be repaired by the ubiquitous enzyme protein carboxyl methyltransferase (4). The importance of this enzyme to normal cellular biology is demonstrated in that mice with an insertional mutation in the protein carboxyl methyltransferase gene die at about 6 weeks of age (5).Another important, but under explored, consequence of isoaspartate formation is the altered immunogenicity of peptides/proteins. Our laboratory has shown that the spontaneous conversion of an aspartic acid to an isoaspartic acid (Fig. 1) induces both T and B cell immunity to model self-antigens (6). The B lymphocyte and antibody-mediated immune response is directed at not only the iso-Asp-modified form of self-antigen but also the native form of the self-antigen (6). Moreover, studies have shown that the post-translational modification of amino acids, such as phosphorylation, glycosylation, or citrullination, in self-antigens can induce an immune response to a self-antigen that was previously ignored by the immune system (7-9).In this study, we describe our efforts to apply this concept to developing immunity to tumor antigens. Many tumor-associated antigens are self-antigens that are often poorly recognized by the immune system. In an effort to make tumor-associated antigens more immunogenic, we introduced an isoaspartate into the peptide sequence of self-tumor proteins. We chose to look at the melanocyte differentiation antigen TRP-2 (tyrosinase-related protein-2) because melanoma continues to be an aggressive and difficult to treat cancer, with over 59,000 new cases d...

show abstract

Deamidation of soluble CD4 at asparagine-52 results in reduced binding capacity for the HIV-1 envelope glycoprotein gp120

Cited by 50 publications

References 34 publications

Comparative vaccine efficacy of different isoforms of recombinant protective antigen against Bacillus anthracis spore challenge in rabbits

Comparative vaccine efficacy of different isoforms of recombinant protective antigen against Bacillus anthracis spore challenge in rabbits

Asparagine Deamidation Perturbs Antigen Presentation on Class II Major Histocompatibility Complex Molecules

Isoaspartyl Post-translational Modification Triggers Anti-tumor T and B Lymphocyte Immunity

Contact Info

Product

Resources

About