When Order Meets Disorder: Modeling and Function of the Protein Interface in Fuzzy Complexes

Abstract

The degree of proteins structural organization ranges from highly structured, compact folding to intrinsic disorder, where each degree of self-organization corresponds to specific functions: well-organized structural motifs in enzymes offer a proper environment for precisely positioned functional groups to participate in catalytic reactions; at the other end of the self-organization spectrum, intrinsically disordered proteins act as binding hubs via the formation of multiple, transient and often non-specific interactions. This review focusses on cases where structurally organized proteins or domains associate with highly disordered protein chains, leading to the formation of interfaces with varying degrees of fuzziness. We present a review of the computational methods developed to provide us with information on such fuzzy interfaces, and how they integrate experimental information. The discussion focusses on two specific cases, microtubules and homologous recombination nucleoprotein filaments, where a network of intrinsically disordered tails exerts regulatory function in recruiting partner macromolecules, proteins or DNA and tuning the atomic level association. Notably, we show how computational approaches such as molecular dynamics simulations can bring new knowledge to help bridging the gap between experimental analysis, that mostly concerns ensemble properties, and the behavior of individual disordered protein chains that contribute to regulation functions.

It takes tau to tango: Investigating the fuzzy interaction between the R2-repeat domain and tubulin C-terminal tails

“…Fnat remains in the [0.4-0.6] range for all trajectory except for one replica (model 84 from the βIII/αI/βIII isotype), a value lower than those observed for protein complexes involving fully folded partners, 50 thus characterizing the fuzzy nature of the tau/tubulin interface. 27 Despite the decrease of the Fnat value, the total number of contacts formed between tau-R2 and tubulin remains stable along time (as shown in Figures 5d-e), with a slightly larger average value in the case of the systems including the tubulin CTTs, as these provide opportunities for more 8 interactions with tau-R2 during the simulations.…”

“…23 For example, in AD brains, tau is found to be phosphorylated on more than 20 positions, mostly serine and threonine residues, and these PTMs impair the protein interaction and its stabilization of microtubules. 24, 25 Due to the disordered nature of tau, the tau/MT assembly is a fuzzy complex , 26, 27 which remains difficult to characterize with classical structural biology approaches. In particular, the disordered CTTs do not appear in the tubulin structures obtained by crystallography or cryo-EM that are currently deposited in the Protein Data Bank 28 (PDB).…”

It Takes Tau to Tango: Investigating the Fuzzy Interaction between the R2-Repeat Domain and Tubulin C-Terminal Tails

“…Fnat remains in the [0.4−0.6] range for all trajectory except for one replica (model 84 from the βIII/αI/βIII isotype), a value lower than those observed for protein complexes involving fully folded partners, 61 thus characterizing the fuzzy nature of the tau/ tubulin interface. 29 Despite the decrease of the Fnat value, the total number of contacts formed between tau-R2 and tubulin remains stable along time (as shown in Figure S5d,e), with a slightly larger average value in the case of the systems including the tubulin CTTs, as these provide opportunities for more interactions with tau-R2 during the simulations.…”

“…The binding of tau on MTs and its propensity to aggregate are affected by PTMs, in particular, the hyperphosphorylation of tau has been shown to be involved in several pathologies . For example, in AD brains, tau is found to be phosphorylated on more than 35 positions, mostly serine and threonine residues, and these PTMs impair the protein interaction and its stabilization of microtubules. − Due to the disordered nature of tau, the tau/MT assembly is a fuzzy complex , , which remains difficult to characterize with classical structural biology approaches. In particular, the disordered CTTs do not appear in the tubulin structures obtained by crystallography or cryo-EM that are currently deposited in the Protein Data Bank (PDB).…”

Modeling the Dynamics of Protein–Protein Interfaces, How and Why?

“…This protein group is estimated to harbor around 25% of disease associated missense mutations [ 152 ], thus making IDPs/IDRs a central therapeutic target. As protein assemblies comprising IDPs or IDRs are very likely to form fuzzy complexes , where one or both partners in the interaction will retain some disorder [ 153 , 154 ], investigating the dynamics of such complexes appears to be an unavoidable step for understanding their function [ 50 , 155 ]. IDPs can also undergo folding-upon-binding transitions when assembling with another protein partner [ 156 ] (see Figure 2 b).…”