Intrinsically disordered proteins and their dynamic multivalent interactions

Published on February 25th, 2020


Protein–protein interactions (PPIs) are fundamental to all cellular functions. The mechanism by which we understand these interactions has evolved since the early “lock and key” model1 to the “induced fit”2 and “conformational selection3 which now takes into account protein dynamics.

In the past thirty years or so however, a new type of protein has become recognized which does not adhere to these established models. The emergence of Intrinsically disordered proteins/regions (IDPs/IDRs) have emerged as a new type of protein that take part in a large proportion of PPIs. Unlike ordered, globular proteins; IDPs have no fixed structure and can interact with binding partners in a multitude of ways. IDPs bind to their partners through, what has been described in the literature as, “fuzzy” interactions and in doing so still retain various degrees of disorder4. The concept of “fuzziness” initially referred to differing levels of structural heterogeneity and flexibility in the complexes formed which included IDPs.

In 2017 a new term was proposed to replace “fuzziness”; dynamic multivalent interaction (DMI). The definition of DMI is when two or more ligand binding sites on the receptor protein bind to two or more binding sites on the ligand5. Presently, DMIs of IDPs result in a dynamic ensemble of protein complexes with heterogeneous conformation, promiscuous binding, stoichiometry and kinetics. In short, these DMIs allow for a plethora of subtly variable interactions that serve in promiscuous functional roles.

Figure 1: Examples of dynamic multivalent interactions (DMI) with IDPs. A) DMI with specific site pairing. B) DMIs facilitating the transport of a protein. C) DMI with binding promiscuity. D) DMI exhibiting heterogeneous stoichiometry. E) Highly fuzzy interactions between a pair of IDPs. Source: Weng & Wang, 20206.

DMI with a specific binding site pairing

As shown in Fig 1A) there is one type of DMI where the binding sites on the IDP and its partner are one-to-one. The binding site pairs may have different affinities and the bound IDP exhibits residual dynamics from binding/rebinding at weak binding sites to local conformational fluctuation. An example of this was recently highlighted in a paper that elucidated the binding affinities of TAZ1/TAD-STAT2 complex. Briefly, the weakly binding part of TAD-STAT2 was found to undergo fast binding/rebinding, which is a property that could be important for binding to multiple partners7.

DMI and heterogeneous stoichiometry

In instances where IDPs and/or their binding partners have multiple binding motifs which can bind to the same or similar target sites/motifs, the interaction could lead to heterogenous stoichiometry of the complex6. The formation of a dynamic complex which possesses heterogenous stoichiometry has now been proven to be a mechanism for tuning transcriptional regulation8. Likewise, there has been a recent study that revealed the DMI between intrinsically disordered tau protein and tubulin results in heterogeneous stoichiometry of tau-tubulin complexes9.

Characterizing IDP DMIs

The PPIs of ordered, regular proteins form a complex network. The added complexity is now being revealed to be due to DMIs between IDPs. Current technologies that measure binding affinities between proteins are geared towards those proteins that are ordered and globular in shape. These are, to a certain extent, ill equipped to characterize the binding between IDPs and regular ordered proteins. This is further compounded by the emerging importance of stoichiometry of complexes, since with IDPs the stoichiometry of these complexes is heterogeneous.

However, the solution to such characterization could be found in microfluidic based technology. Falke et al. used microfluidic diffusional sizing (MDS) to characterize the interaction of an IDP involved in Parkinson’s disease, α-synuclein, with lipid particles10. By using MDS they were able to develop a detailed molecular picture of the protein-lipid interaction in native conditions.


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