This application focuses on the three-dimensional structure of the human platelet integrin aIIb3. Dr. Kunicki proposes that the three-dimensional structure of integrins strongly influences function and immunogenicity. In the case of GPIIb/IIIa, many antigenic sequences are present because of its tertiary structure. An example would be the epitopes of the PlA alloantigen system. These are created by a polymorphism, Leu33/Pro33 of the 3 portion. However, expression of such antigens in the native heterodimer is a reflection of the conformation of the entire 3 subunit. Also, most of the clinically-relevant autoantigens associated with GPIIb/IIIa are """"""""complex-dependent"""""""". Some depend on non-contiguous sequences originating from each subunit, whereas others in the sequence of one subunit can only be expressed when that subunit is complexed with its partner in a functional receptor. GPIIb/IIIa is also an example between the close relationship between antigenicity and function of the protein. Dr. Kunicki has identified and cloned IgG inhibitors of GPIIb/IIIa function which bear the OG idiotype. These IgG inhibitors also share novel recognition sequences common to three specific protein ligands of GPIIb/IIIa, i.e. fibrinogen, vitronectin and von Willebrand factor. Interestingly, antibodies bearing the OG idiotype have evolved to possess recognition motifs also found in genetically related adhesive proteins which can bind to GPIIb/IIIa. As discovery of these relationships continue, we appreciate that the study of GPIIb/IIIa immunogenicity is a steady source of information that can be translated into knowledge of GPIIb/IIIa function.
| Kunicki, Thomas J; Williams, Shirley A; Nugent, Diane J et al. (2012) Mean platelet volume and integrin alleles correlate with levels of integrins ?(IIb)?(3) and ?(2)?(1) in acute coronary syndrome patients and normal subjects. Arterioscler Thromb Vasc Biol 32:147-52 |
| Jacquelin, B; Rozenshteyn, D; Kanaji, S et al. (2001) Characterization of Inherited Differences in Transcription of the Human Integrin alpha 2 Gene. J Biol Chem 276:23518-24 |
| Jacquelin, B; Tarantino, M D; Kritzik, M et al. (2001) Allele-dependent transcriptional regulation of the human integrin alpha2 gene. Blood 97:1721-6 |
| Kunicki, T J; Honda, S; Dawson, B et al. (1995) The P1A alloantigen system is a sensitive indicator of the structural integrity of the amino-terminal domain of the human integrin beta 3 subunit. Blood Cells Mol Dis 21:131-41 |
