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1.
Biochem Soc Trans ; 35(Pt 6): 1574-8, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18031269

ABSTRACT

The formation of oligomeric proteins proceeds at a major cost of reducing the translational and rotational entropy for their subunits in order to form the stabilizing interactions found in the oligomeric state. Unlike site-directed mutations, covalent linkage of subunits represents a generically applicable strategy for enhancing oligomeric stability by reducing the entropic driving force for dissociation. Although this can be realized by introducing de novo disulfide cross-links between subunits, issues with irreversible aggregation limit the utility of this approach. In contrast, tandem linkage of subunits in a single polypeptide chain offers a universal method of pre-paying the entropic cost of oligomer formation. In the present paper, thermodynamic, structural and experimental aspects of designing and characterizing tandem-linked oligomers are discussed with reference to engineering a stabilized tetramer of the oligomerization domain of the human p53 tumour-suppressor protein by tandem dimerization.


Subject(s)
Thermodynamics , Tumor Suppressor Protein p53/chemistry , Tumor Suppressor Protein p53/genetics , Dimerization , Humans , Mutagenesis, Site-Directed , Mutation , Protein Conformation , Protein Denaturation , Protein Folding , Protein Structure, Tertiary
2.
Biochem Soc Trans ; 35(Pt 4): 788-93, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17635149

ABSTRACT

Polycationic macromolecules and cationic peptides acting as PTDs (protein transduction domains) and CPPs (cell-penetrating peptides) represent important classes of agents used for the import and delivery of a wide range of molecular cargoes into cells. Their entry into cells is typically initiated through interaction with cell-surface HS (heparan sulfate) molecules via electrostatic interactions, followed by endocytosis of the resulting complexes. However, the endocytic mechanism employed (clathrin-mediated endocytosis, caveolar uptake or macropinocytosis), defining the migration of these peptides into cells, depends on parameters such as the nature of the cationic agent itself and complex formation with cargo, as well as the nature and distribution of proteoglycans expressed on the cell surface. Moreover, a survey of the literature suggests that endocytic pathways should not be considered as mutually exclusive, as more than one entry mechanism may be operational for a given cationic complex in a particular cell type. Specifically, the observed import may best be explained by the distribution and uptake of cell-surface HSPGs (heparan sulfate proteoglycans), such as syndecans and glypicans, which have been shown to mediate the uptake of many ligands besides cationic polymers. A brief overview of the roles of HSPGs in ligand internalization is presented, as well as mechanistic hypotheses based on the known properties of these cell-surface markers. The identification and investigation of interactions made by glycosaminoglycans and core proteins of HSPGs with PTDs and cationic polymers will be crucial in defining their uptake by cells.


Subject(s)
Antimicrobial Cationic Peptides/metabolism , Membrane Glycoproteins/physiology , Polymers/metabolism , Protein Transport/physiology , Proteoglycans/physiology , Animals , Humans , Protein Sorting Signals/physiology
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