May 2003
Volume 44, Issue 13
ARVO Annual Meeting Abstract  |   May 2003
Molecular Acrobatics: Arrestin Transition into Active Rhodopsin-Binding State
Author Affiliations & Notes
  • V.V. Gurevich
    Pharmacology, Vanderbilt University Medical Center, Nashville, TN, United States
  • Footnotes
    Commercial Relationships  V.V. Gurevich, None.
  • Footnotes
    Support  NIH Grants EY11500 and GM63097
Investigative Ophthalmology & Visual Science May 2003, Vol.44, 1515. doi:
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      V.V. Gurevich; Molecular Acrobatics: Arrestin Transition into Active Rhodopsin-Binding State . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1515.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract: : Purpose: To elucidate molecular mechanism of arrestin transition into high-affinity receptor-binding state. Methods: We used X-ray crystallography, structure-based mutagenesis, and direct binding assay with four functional forms of rhodopsin (dark P-Rh, P-Rh*, dark Rh, and Rh*) to determine functional consequences of various mutations. Results: Mutagenesis data interpreted in the context of high-resolution crystal structure of the basal state of arrestin lead to the conclusion that at least two intramolecular interactions are disrupted by phosphorylated light-activated rhodopsin. These include polar core in the fulcrum of the two-domain arrestin molecule and three-element interaction between C-tail, beta-strand I, and alpha-helix I. Several arrestin elements move relative to each other in the process of its binding to rhodopsin. Receptor-attached phosphates first encounter lysines 14 and 15. These lysines point in opposite directions, so one of them has to flip over, thereby melting beta-strand I and disrupting its interaction with the C-tail and alpha-helix I. Released C-tail moves out, yanking Arg382 out of the polar core. Beta-strand I also moves out to allow lysines 14 and 15 guide the phosphates to the polar core, where they neutralize another positive charge there, that of Arg175. Mutual repulsion of remaining three negative charges (Asp30, Asp296, and Asp303) pushes N- and C-domains apart. Rigid body-like movement of the two domains relative to each other is limited by the length of inter-domain hinge, as evidenced by the fact that deletions of increasing length in the hinge progressively reduce arrestin ability to bind rhodopsin. Finally, alpha-helix I (released from its interactions with both C-tail and beta-strand I) swings out and functions as a reversible membrane anchor stabilizing arrestin-rhodopsin complex. Conclusion: In the process of arrestin activation its "extremities" and its two domains move to "embrace" the cytoplasmic tip of light-activated phosphorylated rhodopsin. Complex rearrangement of arrestin molecule dramatically changes its shape. This conformational change is necessary for arrestin’s high-affinity binding to rhodopsin. It explains unusually high activation energy of arrestin. Major conformational change upon receptor binding also explains arrestin’s ability to interact with various non-receptor partners only when it is bound to the receptor.

Keywords: photoreceptors • protein structure/function • signal transduction 

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