Disease relevance of CDR2

• This C'C'' ridge is homologous to the CDR2 loop of an immunoglobulin variable domain and is known to contain the binding site for human immunodeficiency virus (HIV) coat glycoprotein gp120 [1].
• Defined regions of the CDR2-like region of the T cell antigen CD4 that are implicated in the binding of the surface glycoprotein (gp120) of human immunodeficiency virus type 1 (HIV-1) to CD4+ T lymphocytes have been engineered in place of antigenic site 1 of Sabin type 1 poliovirus [2].
• The CDR2- and CDR3-like domains of CD4 may both contribute to the binding of the HIV envelope necessary for HIV-1 infection and HIV-1-induced cell fusion [3].
• The role of polymorphisms and differential expression of individual V genes in multigenic autoimmune diseases, as well as the organization and expression of individual V genes, can be examined with pairs of oligonucleotides from CDR1 and the 3' end of CDR2, or with probes from the 5' end of CDR2 [4].
• In contrast, a CD4(45-60) peptide, which includes most of the CDR2-related region, was not effective, although the Leu-3a monoclonal antibody (MAb), which recognizes a site near the CDR2-related region, did slightly, but significantly, delay the superinfection kinetics [5].

Psychiatry related information on CDR2

• We have demonstrated the presence of naturally occurring antibodies that bind to the T15H(50-73) peptide in the sera of different strains of mice and also in humans, indicating that the CDR2/FR3 sequence of T15 is a conserved Id determining region [6].
• According to their Clinical Dementia Rating scores, subjects were classified into mild (CDR1; n=11) and moderate (CDR2; n=9) dementia patients [7].

High impact information on CDR2

• These preliminary results suggest that CDR1 and CDR2 may be less variable in structure than their immunoglobulin counterparts, consistent with the idea that they may interact preferentially with the less polymorphic regions of the molecules of the major histocompatibility complex [8].
• Although tumor immunity and autoimmune neuronal degeneration in PCD correlates with a specific antibody response to the tumor and brain antigen cdr2, this humoral response has not been shown to be pathogenic [9].
• Paraneoplastic cerebellar degeneration (PCD) is a disorder in which breast or ovarian tumors express an onconeural antigen termed cdr2, which normally is expressed in cerebellar Purkinje neurons [10].
• Both proteins colocalize in the cytoplasm of adult cerebellar Purkinje neurons, and coimmunoprecipitate from tumor cell lines and cerebellar extracts. cdr2 down-regulates c-Myc-dependent transcription in cotransfection assays, and redistributes Myc protein in the cytoplasm [10].
• Consistent with this observation, independent mutational studies reveal that alanine substitutions of residues in the CDR1 loop of CD8beta have no effect on CD8alphabeta coreceptor function, whereas mutations in CD8beta CDR2 and CDR3 loops abolish CD8alphabeta coreceptor activity [11].

Chemical compound and disease context of CDR2

• Sera or EDTA-blood from 810 ovarian (n = 557) and breast cancer (n = 253) patients were analysed for Yo antibodies by immunoprecipitation, as well as immunofluorescence and immune blots [12].

Biological context of CDR2

• Our results indicate that the signaling events initiated in PBMCs by oligomerization of CD4 at the D1/CDR2-loop can trigger HIV-1 upregulation in infected individuals [13].
• Generation and analysis of random point mutations in an antibody CDR2 sequence: many mutated antibodies lose their ability to bind antigen [14].
• Modulation of promiscuous T cell receptor recognition by mutagenesis of CDR2 residues [15].
• A novel sequence cloned from the 3.7-kb allele differed from VH26 by nine nucleotides and appears to have evolved by gene conversion in CDR2 [16].
• The finding that nucleotide segments present in a D minigene can appear in CDR2 raises the possibility that other minigene segments may be involved in the generation of antibody diversity and complementarity or that nucleotide segments may move from one CDR to another by a gene conversion mechanism [17].

Anatomical context of CDR2

• Importantly, we found that when the anti-dextran V(H) CDR2 replaced CDR2 of an anti-dansyl V(H), the glycosylation site was used, but H chains were withheld in the endoplasmic reticulum and did not traffic to the Golgi apparatus [18].
• The HIV1 envelope glycoprotein gp120 binding site has been previously mapped by genetic studies to the CDR2-like region of the first domain of the CD4 molecule. mAb reactive with epitopes linked to this region (e.g., OKT4A) inhibit both HIV entry into CD4-positive cells and syncytia formation [19].
• For example, the in-to-out activity associated with Cdr1p and Cdr2p is energy-dependent and sensitive to sulphydryl blocking agents such as N-ethylmaleimide (NEM) and cytoskeleton disrupting agent cytochalasin E, while Cdr3p-associated out-to-in activity is energy-dependent but insensitive to NEM and cytochalasin E [20].
• This study was initiated to determine whether regulatory T cells can be induced against a V beta 17a CDR2 peptide (residues 50-68) in SJL/J mice [21].
• In two V4-34 expressing lymphomas, ie a post-germinal center type B cell chronic lymphocytic leukemia (B-CLL) and a follicular lymphoma (FL), internally spliced V(H) gene transcripts were found in which a sequence stretch of 116 bp between the framework region 1 (FR1) and complementarity determining region 2 (CDR2) had been deleted [22].

Associations of CDR2 with chemical compounds

• B-CLL V(H) mutations concentrated in complementarity-determining region 1 (CDR1) and CDR2, which exhibited higher replacement-to-silent ratios (CDR R/S, 4.60; framework region [FR] R/S, 1.72) [23].
• A second mutant, M2, at position 53 (Gly to Asp) in CDR2 of VH increased binding three- to fivefold [24].
• These results suggest that energy-dependent drug efflux associated with increased expression of CDR1 and CDR2 is involved in the fluconazole resistance mechanisms in two of the four isolates, TIMM 3165 and TIMM 3166 [25].
• In contrast, arginine residues in VL CDR2 or VL CDR3 did not enhance CL binding, and in one case may have contributed to inhibition of this binding [26].
• We show that serine 52a, within CDR2, is required for IdHOM expression, homophilic binding, and high avidity binding to cell surface GD3 [27].

Physical interactions of CDR2

• Modelling studies using the three-dimensional coordinates of the V kappa Bence-Jones REI homodimer localize the site in domain I to the C" beta strand within CDR2 but projecting away from the homologues of principle antigen-binding regions CDR 1 and 3 [28].
• PKN interacts with a paraneoplastic cerebellar degeneration-associated antigen, which is a potential transcription factor [29].
• In situ mapping of the gene coding for a leucine zipper DNA binding protein (CDR62) to 16p12-16p13.1 [30].

Enzymatic interactions of CDR2

• PCD17 was phosphorylated by PKN, and the extent of this phosphorylation was enhanced by addition of 40 microM arachidonic acid [29].

Other interactions of CDR2

• Other substitutions in the CDR1 loop and mutations spanning the CDR2 and DE loops had no effect [31].
• Mutations introduced into other loops, including the CDRI-like and CDR2-like regions, had very little effect on CD80 or B70 binding [32].
• Inclusion of the CDR2-like domain of CTLA-4 into HS7 and HS8 did not further increase binding [33].
• In the context of the recently determined atomic structure of CD4, these results further implicate residues in the CDR2-like region and in an adjacent loop in recognition of gp120 [34].
• These results are consistent with a model in which the highly diverse CDR3 loops are the key determinant of specificity in antigen recognition in both T cell receptors (TCR) and antibodies, whereas the germline-encoded CDR1 and CDR2 sequences are much more cross-reactive [35].

Analytical, diagnostic and therapeutic context of CDR2

• Complementarity-determining regions 2 and 3 (CDR2, CDR3) of the immunoglobulin heavy-chain variable region (V(H)) genes were amplified by polymerase chain reaction (PCR), cloned, and sequenced in 8 patients with nodal MZL [36].
• Moreover, the sequence analysis identified a possible site for SED binding of VH4 that includes the solvent-exposed surfaces of 3' CDR2/FR3 and/or FR1 [37].
• Moreover, with a focus on CDR2 peptides that have previously been used to induce regulatory T cells in clinical trials, we established homologous peptide groups, and then identified the optimal amino acid motifs for binding to two alleles, HLA-DRB1*1501 and DRB5*0101, that have been associated with susceptibility to MS [38].
• Inhibition of more than 50% of the polyclonal response to allergen by V beta 3-CDR2 peptide was observed in 16 of 21 donors tested, suggesting that TcR-V beta 3 gene usage may form a major component of the human HDM repertoire and as such offer a suitable target for T cell-directed specific immunotherapy in HDM-allergic individuals [39].
• Vaccination with a CDR2 BV6S2/6S5 peptide in adjuvant induces peptide-specific T-cell responses in patients with multiple sclerosis [40].

References