Biology Reference
In-Depth Information
CHAPTER THREE
Structural Determinants
of Arrestin Functions
Vsevolod V. Gurevich, Eugenia V. Gurevich
Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA
Contents
1.
Introduction
58
2. What the Crystal Structure Reveals, and What It Does Not
59
3. How Do Arrestins Fit Receptors?
60
3.1 Receptor-binding surface of arrestins
61
3.2 The stoichiometry of the complex
63
3.3 Phosphate-binding residues and the phosphate sensor
65
3.4 The conformation of the receptor-bound arrestin
67
3.5 Key determinants of receptor preference
69
4.
Interactions with Other Signaling Proteins
72
4.1 Where do the other partners bind?
72
4.2 The shape of the arrestin
-
MAPK signaling complex
73
4.3 Conformational preferences determine outcomes
73
4.4 Binding and activation do not go hand-in-hand
76
5. Designing Signaling-Biased Arrestin Mutants
77
5.1 Enhanced phosphorylation-independent mutants
78
5.2 Constitutively monomeric arrestins
79
5.3 Manipulating MAPK signaling
80
6. Conclusions: Where Do We Go from Here?
83
Acknowledgments
83
References
83
Abstract
Arrestins are a small protein family with only four members in mammals. Arrestins dem-
onstrate an amazing versatility, interacting with hundreds of different G protein-coupled
receptor (GPCR) subtypes, numerous nonreceptor signaling proteins, and components
of the internalization machinery, as well as cytoskeletal elements, including regular
microtubules and centrosomes. Here, we focus on the structural determinants that
mediate various arrestin functions. The receptor-binding elements in arrestins were
mapped fairly comprehensively, which set the stage for the construction of mutants
targeting particular GPCRs. The elements engaged by other binding partners are only
now being elucidated and in most cases we have more questions than answers.
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