Mapping the transition state for a binding reaction between ancient intrinsically disordered proteins |
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Authors: | Elin Karlsson Cristina Paissoni Amanda M Erkelens Zeinab A Tehranizadeh Frieda A Sorgenfrei Eva Andersson Weihua Ye Carlo Camilloni Per Jemth |
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Institution: | 1.Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden;2.Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy;3.Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran |
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Abstract: | Intrinsically disordered protein domains often have multiple binding partners. It is plausible that the strength of pairing with specific partners evolves from an initial low affinity to a higher affinity. However, little is known about the molecular changes in the binding mechanism that would facilitate such a transition. We previously showed that the interaction between two intrinsically disordered domains, NCBD and CID, likely emerged in an ancestral deuterostome organism as a low-affinity interaction that subsequently evolved into a higher-affinity interaction before the radiation of modern vertebrate groups. Here we map native contacts in the transition states of the low-affinity ancestral and high-affinity human NCBD/CID interactions. We show that the coupled binding and folding mechanism is overall similar but with a higher degree of native hydrophobic contact formation in the transition state of the ancestral complex and more heterogeneous transient interactions, including electrostatic pairings, and an increased disorder for the human complex. Adaptation to new binding partners may be facilitated by this ability to exploit multiple alternative transient interactions while retaining the overall binding and folding pathway. |
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Keywords: | intrinsically disordered proteins phi value analysis transition state protein evolution coupled binding and folding protein folding pre-steady-state kinetics protein complex IDP protein binding |
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