Landscape of intertwined associations in multi-domain homo-oligomeric proteins.

This study charts the landscape of multi-domain protein structures that form intertwined homodimers by exchanging structural domains between subunits. A representative dataset of such homodimers was derived from the Protein Data Bank, and their structural and topological properties were compared to those of a representative set of non-intertwined homodimers. Most of the intertwined dimers form closed assemblies with head-to-tail arrangements, where the subunit interface involves contacts between dissimilar domains. In contrast, the non-intertwined dimers form preferentially head-to-head arrangements, where the subunit interface involves contacts between identical domains. Most of these contacts engage only one structural domain from each subunit, leaving the remaining domains free to form other associations. Remarkably, we find that multi-domain proteins closely related to the intertwined homodimers are significantly more likely than relatives of the non-intertwined versions to adopt alternative intramolecular domain arrangements. In ~40% of the intertwined dimers, the plasticity in domain arrangements among relatives affords maintenance of the head-to-head or head-to-tail topology and conservation of the corresponding subunit interface. This property seems to be exploited in several systems to regulate DNA binding. In ~58%, however, intramolecular domain re-arrangements are associated with changes in oligomeric states and poorly conserved interfaces among relatives. This time, the corresponding structural plasticity appears to be exploited by evolution to modulate function by switching between active and inactive states of the protein. Surprisingly, in total, only three systems were found to undergo the classical monomer to intertwined dimer conversion associated with three-dimensional domain swapping.
(Copyright © 2014. Published by Elsevier Ltd.)