Understanding structural determinants of protein oligomerization

The atomic interactions between subunits in protein assemblies are finely tuned to control affinity as well as quaternary structure. Large protein assemblies are typically held together by weak interactions between individual components but the multiplicity of interactions among the large number of subunits can lead to exquisite specificity. Revealing how molecular interactions are optimized to control both oligomerization state and assembly pathway in protein assemblies is of vital importance for our understanding of biomedically important biological assemblies, as well as for efforts to manipulate them.

The coiled coil is one of most recurring structural motifs in eucarytotic proteins, found in for example transcription factors, motor and skeletal proteins. Coiled coils have been at the focus of much attention over the last 20 years due to their biological significance as well as their suitability as simple model system for studies of oligomerization and binding specificity. Although simple on a sequence level, there is a large amount of structural variation in coiled-coils. They can form homo- or heterocomplexes, align in parallel or antiparallel orientation and form dimeric, trimeric, tetrameric and pentameric assemblies. Our investigations are aimed at understanding how molecular interactions are tuned in coiled coils to encode specific oligomerization states and how at the same time others are selected against.

We use computational protein design methods to change protein sequence in order to modify the oligomerization properties of coiled coils. The redesigned proteins are then characterized experimentally.

 

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