Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs
Abstract
:1. Introduction
2. General Structure and Mechanism of Erbbs
2.1. Similarities and Differences between ErbBs
2.2. The Different Steps of Activation, from Extracellular Ligand Binding to Kinase Activation
2.2.1. Ligand Binding to the ECD and Dimerization
2.2.2. The Transmembrane Helix (TMH) and N-Terminal End of the Juxtamembrane Region (JMA)
2.2.3. The Tyrosine Kinase Domain and Its Activation
2.3. The C-Terminal Tail (CT) and Signal Transduction by Phosphotyrosines
2.3.1. Tyrosine Autophosphorylation Sites
2.3.2. Partners of Phosphorylated Tyrosines of ErbBs
2.3.3. Shortcuts and Pitfall of the Common Signal Transduction Model by CTs
3. CTs of ErbBs, More Than Disordered Ropes with pY Anchors
3.1. Sequence Characteristics of the Four CT-ErbBs
3.2. The Need for Tight Regulation: The Specificity of Tyrosine Phosphorylation Sites
3.3. Regulatory Roles of CT-ErbBs
3.3.1. Interdependence of Phosphorylation Sites
3.3.2. Regulation of Kinase Activity by the CT
3.3.3. The CT Is Involved in ErbB Receptor Trafficking
3.3.4. Possible Regulation of Receptor Clustering by Phase Separation of the CT
3.4. Structural Description Outside of Regions Interacting with the Kinase
3.4.1. Local Structure
3.4.2. Compaction and Long-Range Contacts
3.5. Comparison with the Intracellular Tail of Other RTKs
3.5.1. Inhibition and Activation Mechanisms
3.5.2. An Overlooked Role of Prolines in ErbBs and Other RTKs?
4. Outlook and Outstanding Questions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ALK | Anaplastic Lymphoma Kinase receptor |
CD | Circular Dichroism |
CT | C-terminal Tail |
EGFR | Epidermal Growth Factor Receptor |
ELM | Eukaryotic Linear Motif |
Erbin | ErbB2 Interacting Protein |
FGFR | Fibroblast Growth Factor Receptor |
HER | Human Epidermal growth factor Receptor |
IDP | Intrinsically Disordered Protein |
IDR | Intrinsically Disordered Region |
LLPS | Liquid-liquid phase separation |
LMTK | Lemur Tyrosine Kinase receptor |
LTK | Leukocyte Tyrosine Kinase receptor |
MAPK | Mitogen-Activated Protein Kinases |
MEMO | Mediator of ErbB2-driven cell MOtility |
PI3K | Phosphoinositide 3-kinase |
PLCG1 | Phospholipase C-1 |
PPII | Polyproline type II |
PTB domain | phosphotyrosine binding domain |
PTPN18 | Protein Tyrosine Phosphatase Non-receptor type 18 |
ROR | Retinoid-related Orphan Receptor |
RTK | Receptor Tyrosine Kinase |
SH2 | SRC Homology 2 Domain |
SH3 | SRC Homology 3 Domain |
STAT | Signal Transducers and Activators of Transcription |
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CT-ErbB1 | CT-ErbB2 | CT-ErbB3 | CT-ErbB4 | Average in Disprot [100] | Average in SwissProt [100] | |
---|---|---|---|---|---|---|
Length (residues) | 231 | 268 | 376 | 323 | ND | ND |
Average IUPred score | 0.58 | 0.75 | 0.72 | 0.59 | ND | ND |
Number [%] of Tyr | 9 [3.90] | 9 [3.36] | 14 [3.72] | 19 [5.88] | [2.13] | [3.03] |
Number [%] of Gly | 10 [4.3] | 28 [10.4] | 34 [9.0] | 15 [4.6] | [7.4] | [7.0] |
Number [%] of Pro | 24 [10.4] | 44 [16.4] | 39 [10.4] | 39 [12.1] | [8.1] | [4.8] |
Number [%] of Asp | 20 [8.7] | 21 [7.8] | 19 [5.1] | 21 [6.5] | [5.8] | [5.4] |
Number [%] of Glu | 12 [5.2] | 19 [7.1] | 38 [10.1] | 27 [8.4] | [9.9] | [6.7] |
Number [%] of Arg | 8 [3.5] | 11 [4.1] | 29 [7.7] | 18 [5.6] | [4.8] | [5.4] |
Number [%] of Lys | 6 [2.60] | 5 [1.87] | 7 [1.86] | 15 [4.64] | [7.85] | [5.92] |
Total net charge | −18 | −24 | −21 | −15 | ND | ND |
pI | 4.43 | 4.29 | 5.05 | 4.91 | ND | ND |
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Pinet, L.; Assrir, N.; van Heijenoort, C. Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs. Biomolecules 2021, 11, 1690. https://doi.org/10.3390/biom11111690
Pinet L, Assrir N, van Heijenoort C. Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs. Biomolecules. 2021; 11(11):1690. https://doi.org/10.3390/biom11111690
Chicago/Turabian StylePinet, Louise, Nadine Assrir, and Carine van Heijenoort. 2021. "Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs" Biomolecules 11, no. 11: 1690. https://doi.org/10.3390/biom11111690