Curr. Issues Mol. Biol., Volume 13, Issue 1 (January 2011) – 2 articles

The pathogenesis of common diseases, such as metabolic diseases, is caused by the complex and individual interplay of many susceptibility genes, which necessitates both personalized diagnosis and therapy. Small-molecule drugs which adequately address the multiple tissue-specific target proteins affected probably will not become available in near future. In contrast, therapeutic proteins, such as growth factors and antibodies, specifically replacing or inactivating the corresponding susceptibility gene products, are currently being identified with increasing efficacy. However, the failure to be administered by the oral route and to reach the cytoplasm of the diseased cells typically prevents their therapeutic use. Recent developments suggest that these limitations may be overcome by encapsulation of therapeutic proteins into nanoparticles or their covalent modification with glycolipid (glycosylphosphatidylinositol, GPI) structures. These act as membrane anchors for so-called GPI-anchored proteins and direct certain attached passenger proteins from lipid raft areas of the plasma membrane via cytoplasmic lipid droplets into small vesicles. These leave the donor cells and transfer the GPI-anchored proteins into the cytoplasm of acceptor cells. This pathway may enable the transport of therapeutic proteins across the intestinal barrier into the circulation and eventually across the plasma membrane of the diseased target cells. For therapy, a number of challenges remains to be tackled, in particular, control of release from the GPI anchor which determines the pharmacokinetic and pharmacodynamic profiles. Together these findings nourish the hope that oral path finding to drug targets by encapsulation and covalent modification of therapeutic proteins may enable personalized therapy of common diseases. Full article

Bacterial histone-like HU proteins are critical to maintenance of the nucleoid structure. In addition, they participate in all DNA-dependent functions, including replication, repair, recombination and gene regulation. In these capacities, their function is typically architectural, inducing a specific DNA topology that promotes assembly of higher-order nucleo-protein structures. Although HU proteins are highly conserved, individual homologs have been shown to exhibit a wide range of different DNA binding specificities and affinities. The existence of such distinct specificities indicates functional evolution and predicts distinct in vivo roles. Emerging evidence suggests that HU proteins discriminate between DNA target sites based on intrinsic flexure, and that two primary features of protein binding contribute to target site selection: The extent to which protein-mediated DNA kinks are stabilized and a network of surface salt-bridges that modulate interaction between DNA flanking the kinks and the body of the protein. These features confer target site selection for a specific HU homolog, they suggest the ability of HU to induce different DNA structural deformations depending on substrate, and they explain the distinct binding properties characteristic of HU homologs. Further divergence is evidenced by the existence of HU homologs with an additional lysine-rich domain also found in eukaryotic histone H1. Full article