Biomedical subjects

Enrique Vargas-Madrazo

Publications and source records attributed to Enrique Vargas-Madrazo.

5 recordsLinked to original sources

PubMed2005

Substitution patterns in alleles of immunoglobulin V genes in humans and mice.

Immunoglobulins (Igs) constitute a subfamily of rapidly evolving proteins. It is postulated that this characteristic is due mainly to the participation of these proteins in highly diverse functions of recognition and defense. Although this vision of rapid evolution in Igs is widely accepted, various studies have demonstrated that diverse and contradictory forces not yet completely understood converge in the evolution of these receptors. In a recent study of the substitution patterns in the alleles that form the human IGHV locus, we found that the variation in genetic and structural information does not occur homogeneously among the different genes, nor among the regions and positions conforming said locus. In view of these results and of the importance of a better understanding of the basic evolutionary process in specific receptors (such as Igs) for both immunology and molecular evolution, it is important to explore the nature of the diversification process in these proteins in detail. In this work, therefore, we analyzed the substitution patterns in all the alleles reported for loci IGKV and IGLV in humans and mice, and we compared the results with those previously observed in the human IGHV locus. We found that the process of evolutionary variation of the Igs reflect the diversity of selective pressures operating on the different loci, genes, sub-regions and positions; for example, diversification through substitution is generally centered on CDRs, but only few positions inside the CDRs were frequently substituted. In spite of this general tendency, it is possible to observe differences in the degree of diversification among loci, families and genes. These tendencies to modify only certain attributes of IGV genes seem to be in agreement with differential strategies associated with the restrictions of the molecular immune recognition mechanism. The complexity of the evolutionary patterns observed in this study leads us to think that the predispositions observed herein may also be due in part to processes of DNA dynamics.

Alleles↗

PubMed2005

Novel substitution polymorphisms of human immunoglobulin VH genes in Mexicans.

It has been proposed that the defense and recognition functions of the immune system, especially those mediated by antibodies, require a great diversity of receptors. Nonetheless, functional and structural evidence has demonstrated the presence of restrictions, both in the use of the repertoire and in the recognition of antigens. Fifty-one functional genes have been described in the IghV locus; however, there is a variety of evidences indicating that only a small fraction of the immunoglobulin genes plays a central role in determining the fundamental properties of the antibody repertoire of the immune system. On the basis of this functional and structural information, we selected four IghV genes and characterized their polymorphism in a sample of Mexican individuals. We also analyzed the implications for the recognition mechanism of the substitutions found in the sequenced alleles. We found that diversification through allelism varies from segment to segment, both in the amount of alleles encountered and in the nature and distribution of mutations in the codifying zone, which might depend on its importance for the repertoire. Such functional characteristics may be useful in the interpretation of differential gene usage in certain physiological, ontological, and/or pathological conditions.

Alleles↗

PubMed2004

Structural analysis of substitution patterns in alleles of human immunoglobulin VH genes.

The diversity in repertoires of antibodies (Abs) needed in response to the antigen challenge is produced by evolutionary and somatic processes. The mechanisms operating at a somatic level have been studied in great detail. In contrast, neither the mechanisms nor the strategies of diversification at an evolutionary level have yet been understood in similar detail. Particularly, the substitution patterns in alleles of immunoglobulin genes (Igs) have not been systematically studied. Furthermore, there is a scarcity of studies which link the analysis at a genetic level of the diversification of repertoires with the structural consequences at the protein level of the changes in DNA information. For the purpose of systematically characterizing the strategies of evolutionary diversification through sequence variation at alleles, in this work, we built a database for all the alleles of the IGHV locus in humans reported until now. Based on these data, we performed diverse analyses of substitution patterns and linked these results with studies at the protein level. We found that the sequence diversification in different alleles does not operate with equal intensity for all V genes. Our studies, both of the number of substitutions and of the type of amino acid change per sub-segment of the V-REGION evidenced differences in the selective pressure to which these regions are exposed. The implications of these results for understanding the evolutionary diversification strategies, as well as for the somatic generation of antibody repertoires are discussed.

Alleles↗

PubMed2002

Modifications to canonical structure sequence patterns: analysis for L1 and L3.

The conformation of five of the six hypervariable loops that form the antigen-binding site of antibodies is limited to a small set of structures designated as canonical structures. The canonical structure model has been constituted as a fundamental tool for the modeling of antibodies. The detailed study of tens of crystallographic structures of antibodies has shown the validity of this model in the great majority of cases. The robustness of the forecast capacity of this model depends fundamentally on the precision with which the sequence patterns that characterize each canonical structure form can be defined. Nevertheless, due to the enormous quantity of structural information about antibodies generated during the last decade, it is difficult to avoid mistakes or confusion in the model. In the present work, we propose some corrections to the model for loops L1 and L3 that permit defining sequence patterns that avoid confusion and make better forecasting of the canonical structure model possible.

Animals↗

PubMedDate not supplied

An improved model of association for VH-VL immunoglobulin domains: asymmetries between VH and VL in the packing of some interface residues.

The antibody-binding site is formed as a result of the association between VH and VL domains. Several studies have shown that this association plays an important role in the mechanism of antigen-antibody interaction (Stanfield et al. Structure 1: 83-93, 1993). Considering this, we propose that variations in the VH-VL association are part of the diversification strategy of the antibody repertoires. Previously, a model of association for VH-VL domains based on geometrical characteristics of the packing at the interface was developed by Chothia et al. (J. Mol. Biol. 186: 61-663, 1985). This model includes a common association form for antibodies and a three-layer structure for the interface. In the present work, a complementary model is introduced to account for the general geometrical restrictions of the VH-VL interface, and particular arrangements related to the chemical properties or the side-chain orientations of participating residues. Groups of residues assume common side-chain orientations, which are apparently related to particular functions of different interface zones. Analyses of amino acid usage and network are in agreement with the side-chain orientation patterns. Based on these observations, a three-zone model has evolved to illuminate geometrical and functional restrictions acting over the VH-VL interface. Additionally, this study has revealed the asymmetrical relationships between VH and VL residues important for the association of the two domains.

Animals↗