Side-chain interactions form late and cooperatively in the binding reaction between disordered peptides and PDZ domains

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S Raza Haq, Celestine N Chi, Anders Bach, Jakob Dogan, Åke Engström, Greta Hultqvist, O. Andreas Karlsson, Patrik Lundström, Linda Celeste Montemiglio, Kristian Strømgaard, Stefano Gianni, Per Jemth

Intrinsically disordered proteins are very common and mediate numerous protein-protein and protein-DNA interactions. While it is clear that these interactions are instrumental for the life of the mammalian cell, there is a paucity of data regarding their molecular binding mechanisms. We have here used short peptides as a model system for intrinsically disordered proteins. Linear free-energy relationships based on rate and equilibrium constants for the binding of these peptides to ordered target proteins, PDZ domains, demonstrate that native side-chain interactions form mainly after the rate-limiting barrier for binding, in a cooperative fashion. This finding suggests that these disordered peptides first form a weak encounter complex with non-native interactions. The data do not support the recent notion that the affinities of intrinsically disordered proteins towards their targets are generally governed by their association rate constants. Instead, we observe the opposite for peptide-PDZ interactions, namely that changes in Kd correlate with changes in koff.
OriginalsprogEngelsk
TidsskriftJournal of the American Chemical Society
Vol/bind134
Udgave nummer1
Sider (fra-til)599-605
ISSN0002-7863
DOI
StatusUdgivet - jan. 2012

ID: 35412490