Domain-like aggregates

Scheme 1 The domains of nanomedicine including aspects of pharmaceutical nanotechnology. There are of course no strict boundaries between the subdomains. The links shown here are deliberate. Drug nanocrystals, for example, could be considered, like aggregates of therapeutic peptides and proteins, to be their own carriers systems, predominantly widiout additives.

As discussed in the following sections, even soluble surfactants can form inhomogeneous adsorption layers. The origin of such inhomogeneities is not fully understood. It could be possible that it is a feature of mixed adsorption layers, formed by commercial surfactants of low purity or by mixtures of particular composition. Such domain-like structures could be formed due to remarkable differences in the interaction strength within the adsorption layer. The formation of 2- and 3-dimensionaI aggregates at interfaces is known from studies of insoluble monolayers (Mohwald et al. 1986 and Barraud et al. 1988, Vollhardt 1993). First dynamic models of aggregate formation in insoluble monolayers were theoretically described by Retter Vollhardt (1993) and Vollhardt et al. (1993). These simple and new, more... 

Coacervation occurs in tropoelastin solutions and is a precursor event in the assembly of elastin nanofibrils [42]. This phenomenon is thought to be mainly due to the interaction between hydro-phobic domains of tropoelastin. In scanning electron microscopy (SEM) picmres, nanofibril stmc-tures are visible in coacervate solutions of elastin-based peptides [37,43]. Indeed, Wright et al. [44] describe the self-association characteristics of multidomain proteins containing near-identical peptide repeat motifs. They suggest that this form of self-assembly occurs via specific intermolecular association, based on the repetition of identical or near-identical amino acid sequences. This specificity is consistent with the principle that ordered molecular assembhes are usually more stable than disordered ones, and with the idea that native-like interactions may be generally more favorable than nonnative ones in protein aggregates. 

Like all immunoreceptor family members, FceRI lacks intrinsic tyrosine kinase activity. IgE and antigen-induced crosshnking of FceRI initiates a complex series of phosphate transfer events via the activation of non-receptor Src, Syk and Tec family protein tyrosine kinases (fig. 1). The Src family kinase Lyn, which associates with the FceRI p subunit in mast cells, transphosphorylates neighboring FceRI ITAMs after receptor aggregation [7, 26]. Once phosphorylated, the p chain ITAM binds to the SH2 domain of additional Lyn molecules, while the phosphorylated y chain ITAM recruits Syk to the receptor complex, where it is activated by both autophosphorylation and phosphorylation by Lyn [2, 7,15, 26]. 

In the case of amphiphilic molecules, characterized by the coexistence of spatially separated apolar (alkyl chains) and polar moieties, both parts cooperate to drive the intermolecular aggregation. This simple but pivotal peculiarity makes amphiphilic molecules soluble in both polar and apolar solvents and able to realize, in suitable conditions, an impressive variety of molecular aggregates characterized by spatially separated apolar and polar domains, local order at short times and fluidity at long times, and differences in size, shape (linear or branched chains, cyclic or globular aggregates, extended fractal-like molecular networks), and lifetime. 

In addition to its role as the P-subunit of PHY, PDI acts independently by catalysing thiol/protein disulphide interchange. The role of PDI as the P-subunit in prolyl 4-hydroxylase is not related to its disulphide isomerase activity and experiments where the vertebrate PDI was mutated in both thioredoxin-like active domains had no effect on tetramer assembly (Vuori et al., 1992). PDI appears to function as a molecular chaperone, retaining the a-subunits in the correct catalytically active, non-aggregated form in the ER-lumen (John et al, 1993). Dissociation of the P-subunits results in insoluble aggregates of the a-subunits, analogous to a-subunits expressed in the absence of PDI. An additional function of PDI in the complex is to maintain the ER luminal location of the a-subunits, since deletion of the ER retention signal from PDI results in the secretion of the complex (Vuori et al., 1992). 

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