Publications (2)5.86 Total impact
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Article: RGD sequences in several receptor proteins: novel cell adhesion function of receptors?
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ABSTRACT: In the process of homology modelling of the 3-dimensional structure of alleles of the human histocompatibility protein HLA-DQ, we discovered that its RGD tripeptide (beta 167-169) forms part of a loop. A search through protein sequence data bases, revealed this cell adhesion motif in 67 integral plasma membrane proteins (in 48 extracellularly, and in the remaining 19 intracellularly), which are bona fide receptors, and none of them has thus far been considered as a cell adhesion protein. The 3-dimensional structure of one of these, the rat neonatal Fc receptor, is known and its extracellular RGD sequence is in an adhesion-like loop, a fact that went unnoticed in the original papers. In a few other cases, e.g. rat and mouse growth hormone receptor, and mouse CD40 ligand, homology modelling by ourselves and others reveals that the said sequences are part of a loop, in similarity to all RGD sequences found in proteins with established adhesion function and known 3-dimensional structure. Likewise, inspection of all known protein 3-dimensional structures containing an RGD sequence, and not having a documented cell adhesion function (total of 65 separate entries) shows that such sequence is mostly (52/65 or 80% of cases) part of a loop. We therefore call attention to these surprising findings, discuss the possible cell adhesion role of these receptor proteins, and draw an analogy from the two well characterised examples, that of soluble IGF binding protein 1 and the transcriptional activator protein Tat of HIV, where their RGD sequences have been shown by site-directed mutagenesis to participate in cell-adhesion interactions, without prior knowledge of the location of the tripeptide, or the 3-dimensional structure of the respective protein.International Journal of Biological Macromolecules 02/1998; 22(1):51-7. · 2.45 Impact Factor -
Article: Novel structural features of the human histocompatibility molecules HLA-DQ as revealed by modeling based on the published structure of the related molecule HLA-DR.
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ABSTRACT: Structural modeling of the HLA-DQ molecules, a group of human histocompatibility antigens linked to autoimmune diseases and immunosuppression-based on the structure of the homologous molecule DR1, has revealed an overall shape typical of the class II histocompatibility molecules, yet with several novel features. These are unique to HLA-DQ and include: (1) an antigen-binding groove with a polymorphic first pocket and anchoring in the second and/or fifth pocket, (2) a polymorphic beta 49-56 dimerization patch, and (3) in many alleles a prominent Arg-Gly-Asp loop (beta 167-169), probably involved in cell adhesion, as it exhibits an architecture similar to identical sequences involved in such function. The alpha 2 beta 2 dimerisation domain and the CD4-binding region are nearly identical to their counterparts in the structure of HLA-DR1. The significance of the few substitutions in the CD-4 binding region remains to be evaluated. The polymorphic first antigen-binding pocket and the anchoring in the second and/or fifth pocket point to differences in antigenic fragment selection compared to HLA-DR antigens, while the polymorphism in the beta 49-56 homodimerization patch implies either ease of spontaneous or T lymphocyte receptor-induced homodimerization or difficulty in the latter. As homodimerization appears to be an obligatatory intermediate in the activation of cognate DQ-restricted T lymphocytes and DQ-bearing antigen-presenting cells, the dimerization properties of DQ allels signify the respective ease or difficulty of activation of these two cell types. The RGD loop confers cell adhesion possibilities to those DQ allels that possess it, yet its putative ligand cannot be defined at present. These features are suggestive of the probable mechanisms through which some of the unique immunological properties of the HLA-DQ molecules are effected.Journal of Structural Biology 117(2):145-63. · 3.41 Impact Factor
