Abstract
Structural disorder is an essential ingredient for function in many proteins and protein complexes. Fuzzy complexes describe the many instances where disorder is maintained as a critical element of protein interactions. In this minireview we discuss how intramolecular fuzzy interactions function in signaling complexes. Focussing on the Src family of kinases, we argue that the intrinsically disordered domains that are unique for each of the family members and display a clear fingerprint of long range interactions in Src, might have critical roles as functional sensor or effectors and mediate allosteric communication via fuzzy interactions.
Highlights
Specialty section: This article was submitted to Structural Biology, a section of the journal Frontiers in Molecular Biosciences
Disordered proteins (IDP) or proteins with long intrinsically disordered regions (IDR) form a significant portion of the proteome of eukaryotes and are specially prevalent in signaling and regulation complexes (Iakoucheva et al, 2002)
Entropy contains “local” components associated to the degree of structure achieved by the contact regions of the two interacting partners, as well as more global contributions of which we may distinguish (i) the effect of regions that can remain highly flexible in the complex, (ii) the possible preexistence of long range intramolecular contacts restricting the conformational freedom in the free IDR, and (iii) the configurational entropy arising from multiple alternative binding poses (“microstates”) contributing to the bound state
Summary
Miguel Arbesú*, Guillermo Iruela, Héctor Fuentes, João M. In a typical divide-and-conquer approach, the structure-function analysis proceeds through the characterization of the individual domains followed by the study of their mutual interactions. This approach makes a clear distinction between the “functional” domains and the linkers separating them. The current view of protein-protein interactions is quite dynamic and intrinsically disordered regions (IDR) are increasingly recognized as key players. In this minireview we shall summarize some important aspects of (intermolecular) protein binding by disordered proteins and extend them to the case of interdomain (i.e., intramolecular) binding using the c-Src family of kinases as an example
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