Understanding eukaryotic linear motifs and their role in cell signaling and regulation

Abstract

It is now clear that a detailed picture of cell regulation requires a comprehensive understanding of the abundant short protein motifs through which signaling is channeled. The current body of knowledge has slowly accumulated through piecemeal experimental investigation of individual motifs in signaling. Computational methods contributed little to this process. A new generation of bioinformatics tools will aid the future investigation of motifs in regulatory proteins, and the disordered polypeptide regions in which they frequently reside. Allied to high throughput methods such as phosphoproteomics, signaling networks are becoming amenable to experimental deconstruction. In this review, we summarise the current state of linear motif biology, which uses low affinity interactions to create cooperative, combinatorial and highly dynamic regulatory protein complexes. The discrete deterministic properties implicit to these assemblies suggest that models for cell regulatory networks in systems biology should neither be overly dependent on stochastic nor on smooth deterministic approximations.

Sequence Determinants of a Microtubule Tip Localization Signal (MtLS)

“…The EB1 binding affinities of many isolated MtLS sequences that we have tested are in the low/medium micromolar range, the best binders displaying a dissociation constant around 1 M. Such rather weak interactions are typical for short linear motifs that organize highly dynamic protein networks (43,44), reminiscent to the ones orchestrated by EBs at growing microtubule tips (4, 12-14). Interestingly, we found a good correlation between EB binding affinity and microtubule tip tracking activity in cells, further underpinning the conclusion that the EB-SXIP interaction is the underlying mechanism used by many ϩTIPs to target the growing microtubule plus-end.…”

Exploring the binding diversity of intrinsically disordered proteins involved in one‐to‐many binding

“…As suggested by others, through parallel or convergent evolution, such MoRFs can exist as conserved functional motifs or regions among various species, such as human, mouse, yeast, E. coli, or even viruses. 79 As pointed out previously, 77 such short linear motifs are amenable to convergent evolution due to the limited number of mutations that are necessary for the generation of a useful motif. In fact, motifs are commonly used as adding new functional modules within a proteome, especially in higher eukaryotes.…”

“…47,75,77,78 Instead, our approach here is to investigate fewer MoRF examples, but in greater detail in order to develop a deeper understanding of how IDPs can alter their conformations so as to be able to bind to structurally distinct partners. Our observations demonstrated that, in general, conformation flexibility allows for both subtle and complex structural variation, thereby enabling the same sequence to transform onto the diverse and distinctively shaped binding sites provided by their partners.…”

From protein sequence to dynamics and disorder with DynaMine

“…DynaMine has the ability to outline molten globule regions (for example, NCBD or CBP) embedded in a more disordered structural environment. IDPs often recognize their binding partners via short continuous sequence motifs, which are frequently defined by local sequence conservation 38,39 and structural bias towards the bound conformational state [6][7][8] . DynaMine seems to be capable of picking up locally reduced dynamics in these regions, which appear as peaks in the prediction.…”