Book of Abstracts: Albany 2003
June 17-21 2003
Structural Weaknesses and Cation-π Interactions in Proteins. A Possible Link with 3D Domain Swapping
Three-dimensional domain swapping occurs when two or more identical proteins exchange identical parts of their structure to generate an oligomeric unit. It affects proteins with diverse sequences and structures, and is expected to play important roles in evolution, functional regulation and even conformational diseases. We searched for traces of domain swapping in the protein sequence, by means of algorithms that predict the structure and stability of proteins using database-derived potentials. Regions whose sequences are not optimal with regard to the stability of the native structure, or showing marked intrinsic preferences for non-native conformations in absence of tertiary interactions were detected in most known domain-swapping proteins. These regions are often located in areas crucial in the swapping process, such as the hinge loop linking two domains, the closed interface, between two intertwined chains, or the open interface, between two domains, and are likely to influence it on a kinetic or thermodynamic level. In addition, cation-π interactions were frequently observed to zip up the edges of the closed and open interfaces, or to involve hinge loop residues, thereby modulating stability. On the basis of these observations, we proposed a set of mutations altering the swapping propensities, whose experimental characterization would contribute to refine our in silico derived hypotheses.
Representation of the non-swapped (a ? pdb code: 1qlx) and swapped (b ? pdb code: 1i4m) forms of the human prion protein. The main chains are colored in red, with the swapped parts in dark blue and the hinge loops in purple. The region depicted in green (residues 181-194) presents, in absence of tertiary contacts, a strong preference for an extended conformation, although it is part of an helix in the monomeric form. In the swapped form, the C-terminal part of this helix is disrupted to provide a link between the two domains, and residues 190-194 adopt an extended conformation. Cation-p interactions are depicted in yellow, in one domain only for sake of clarity. The images were generated with InsightII (Accelrys, Inc.).
Yves Dehouck *
Ingénierie Moléculaire et Biomoléculaire