Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs

Abstract

ErbBs are receptor tyrosine kinases involved not only in development, but also in a wide variety of diseases, particularly cancer. Their extracellular, transmembrane, juxtamembrane, and kinase folded domains were described extensively over the past 20 years, structurally and functionally. However, their whole C-terminal tails (CTs) following the kinase domain were only described at atomic resolution in the last 4 years. They were shown to be intrinsically disordered. The CTs are known to be tyrosine-phosphorylated when the activated homo- or hetero-dimers of ErbBs are formed. Their phosphorylation triggers interaction with phosphotyrosine binding (PTB) or Src Homology 2 (SH2) domains and activates several signaling pathways controling cellular motility, proliferation, adhesion, and apoptosis. Beyond this passive role of phosphorylated domain and site display for partners, recent structural and function studies unveiled active roles in regulation of phosphorylation and interaction: the CT regulates activity of the kinase domain; different phosphorylation states have different compaction levels, potentially modulating the succession of phosphorylation events; and prolines have an important role in structure, dynamics, and possibly regulatory interactions. Here, we review both the canonical role of the disordered CT domains of ErbBs as phosphotyrosine display domains and the recent findings that expand the known range of their regulation functions linked to specific structural and dynamic features.

Keywords: EGFR; ErbB; HER; intrinsic disorder; receptor tyrosine kinases; signal transduction.

Figure 1

ErbBs structure and signaling mechanism. (A) Schematic representation of the role of ErbBs in signal transduction. Only some of the signaling pathways are represented here. The cross on ErbB3 kinase domain indicates its weak activity. ErbB2 is shown in its constitutively dimerization-prone conformation. (B) The different steps of ErbB signal transduction, with the example of ErbB1 ligand EGF triggering ErbB1/2 heterodimerization, ErbB1 kinase activation, and Ras/MAPK pathway activation through binding of the adaptor protein Grb2. (C) Model structure of activated full-length EGFR from structures and models of individual domains. A model for the C-terminal tail (CT) is lacking. Reproduced with permission from [31]. (D) Overall domain organization of EGFR and ErbB2 with numbering. For the ECD, in orange are leucine-rich repeat domains (domains I and III), and in blue are cystein-rich domains (domains II and IV). The Uniprot numbering is used (unless otherwise stated) in this review. For EGFR, the alternative numbering sometimes used excludes the signal peptide in the N-terminus. For ErbB2, the alternative numbering is that of rat ErbB2 (neu). In the CT, all tyrosine positions are indicated, with * on the ones that are known autophosphorylation sites.

Figure 2

Inactive-to-active transition of ErbB kinase dimer and role of C-terminal tail. (A) Kinase monomers in inactive and active states, with change seen in activation loop conformation (black). Figure created using PyMOL (PyMOL Molecular Graphics System, Version 2.0, Schrödinger, LLC, New York, NY, USA). (B) Inactive and active kinase dimers. In the inactive dimer [31] (PDB 3GT8), the C-terminal tail interacts with the C-lobe of the same monomer (interaction region shown in a dotted rectangle). In the active dimer [62] (PDB 2GS2), the same region of the C-lobe of the activator kinase monomer interacts with the JMB segment of the receiver kinase monomer.

Figure 3

Phosphorylated tyrosines of ErbBs. (A) Review of different studies on relative levels of phosphorylation of 8 (out of 9) tyrosines of EGFR C-terminal tail. —, +, ++ and +++: different levels of phosphorylation, from low to high. *: greatly enhanced by ErbB2 expression. “/” indicates different results in different studies. “ND”, not determined. Adapted from [79]. (B) Phosphotyrosine interactome of C-terminal tails of ErbB receptors. Adapted from [84].

Figure 4

Experimental structures of CT-ErbB peptides (in red) bound to partners (in blue). Each (phospho)tyrosine mainly involved in binding is in orange and its number in the sequence is indicated. Figure created using PyMOL.

Figure 5

Summary of all experimentally confirmed or potential regulation roles of C-terminal tails of ErbBs (red), in addition to “canonical” roles of the CT (black). Each CT feature (in the main circle) can influence other ones and create regulation loops.