Enhancement of oligomeric stability by covalent linkage and its application to the human p53tet domain: thermodynamics and biological implications.
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.
Poon
G M K
GM
Division of Cancer Genomics and Proteomics, Ontario Cancer Institute, Princess Margaret Hospital, 610 University Avenue, Toronto, ON, Canada M5G 2M9. gpoon@uhnres.utoronto.ca
D019281:Dimerization; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D013816:Thermodynamics; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics*
D016159:Tumor Suppressor Protein p53