In eukaryotic cells, proteins are often targeted to specfic compartments. This targeting ususally depends on signals within the proteins themselves that are recognized by specific intracellular receptors. One compartment of interest are peroxisomes. Most proteins are targeted to peroxisomes by virtue of sequences found at their carboxyl-termini that approximate the sequence -SerLysLeu. These are recognized by the protein Pex5p. Sequence variants in the proteins that participate in this protein targeting process have been associated with developmental disorders termed peroxisome biogenesis disorders. Through studies of the binding of a series of peptides to wild-type human Pex5p as well as two disease-associated sequence variants, we have developed a model that rationalizes the peroxisome targeting properties of many proteins within the human proteome. This model provides an explanation of the variation in the severity of disease with Pex5p sequence variation.? ? Some protein-protein interactions within cells are mediated by metal ions such as zinc that bridge between the two proteins. One particular example of this sort of interaction involves the T-cell proteins Lck, CD4, and CD8alpha. The interactions between Lck and CD4 and between Lck and CD8alpha are mediated by short sequences that come together around zinc ion with each protein contributing two cysteine residues to the zinc coordination environment. Chemical considerations suggest that these sequences from each protein should come together around a metal ion to form homodimeric complexes. Using a variety of methods including visible spectroscopy with cobalt as a substitute for zinc, gel filtration chromatography, and proton nuclear magnetic resonance spectroscopy, we demonstrated that such homodimeric complexes do, indeed, form, but that there are considerable preferences for the formation of heterodimeric complexes even with short peptides. These studies lay the foundation for future studies to understand the mechanistic basis of this specificity.
| Martin, Gregory G; Hostetler, Heather A; McIntosh, Avery L et al. (2008) Structure and function of the sterol carrier protein-2 N-terminal presequence. Biochemistry 47:5915-34 |
| Maynard, Ernest L; Berg, Jeremy M (2007) Quantitative analysis of peroxisomal targeting signal type-1 binding to wild-type and pathogenic mutants of Pex5p supports an affinity threshold for peroxisomal protein targeting. J Mol Biol 368:1259-66 |
