DOI: 10.1042/bj20070005. Mapping binding sites for the PDE4D5 cAMP-specific phosphodiesterase to the N- and C-domains of β-arrestin using spot-immobilized peptide arrays

Mapping binding sites for the PDE4D5 cAMP-specific phosphodiesterase to the N- and C-domains of β-arrestin using spot-immobilized peptide arrays

10.1042/bj20070005

Crossref journal-article

Portland Press Ltd.

Biochemical Journal (288)

Abstract

β2-ARs (β2-adrenoceptors) become desensitized rapidly upon recruitment of cytosolic β-arrestin. PDE4D5 (family 4 cAMP-specific phosphodiesterase, subfamily D, isoform 5) can be recruited in complex with β-arrestin, whereupon it regulates PKA (cAMP-dependent protein kinase) phosphorylation of the β2-AR. In the present study, we have used novel technology, employing a library of overlapping peptides (25-mers) immobilized on cellulose membranes that scan the entire sequence of β-arrestin 2, to define the interaction sites on β-arrestin 2 for binding of PDE4D5 and the cognate long isoform, PDE4D3. We have identified a binding site in the β-arrestin 2 N-domain for the common PDE4D catalytic unit and two regions in the β-arrestin 2 C-domain that confer specificity for PDE4D5 binding. Alanine-scanning peptide array analysis of the N-domain binding region identified severely reduced interaction with PDE4D5 upon R26A substitution, and reduced interaction upon either K18A or T20A substitution. Similar analysis of the β-arrestin 2 C-domain identified Arg286 and Asp291, together with the Leu215–His220 region, as being important for binding PDE4D5, but not PDE4D3. Transfection with wild-type β-arrestin 2 profoundly decreased isoprenaline-stimulated PKA phosphorylation of the β2-AR in MEFs (mouse embryo fibroblasts) lacking both β-arrestin 1 and β-arrestin 2. This effect was negated using either the R26A or the R286A mutant form of β-arrestin 2 or a mutant with substitution of an alanine cassette for Leu215–His220, which showed little or no PDE4D5 binding, but was still recruited to the β2-AR upon isoprenaline challenge. These data show that the interaction of PDE4D5 with both the N- and C-domains of β-arrestin 2 are essential for β2-AR regulation.

Bibliography

Baillie, G. S., Adams, D. R., Bhari, N., Houslay, T. M., Vadrevu, S., Meng, D., Li, X., Dunlop, A., Milligan, G., Bolger, G. B., Klussmann, E., & Houslay, M. D. (2007). Mapping binding sites for the PDE4D5 cAMP-specific phosphodiesterase to the N- and C-domains of Î²-arrestin using spot-immobilized peptide arrays. Biochemical Journal, 404(1), 71â80.

Authors 12

George S. Baillie (first)
David R. Adams (additional)
Narinder Bhari (additional)
Thomas M. Houslay (additional)
Suryakiran Vadrevu (additional)
Dong Meng (additional)
Xiang Li (additional)
Allan Dunlop (additional)
Graeme Milligan (additional)
Graeme B. Bolger (additional)
Enno Klussmann (additional)
Miles D. Houslay (additional)

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Dates

Type	When
Created	18 years, 3 months ago (April 27, 2007, 4:02 a.m.)
Deposited	3 years, 9 months ago (Nov. 22, 2021, 8:47 a.m.)
Indexed	1 month, 1 week ago (July 14, 2025, 11:26 p.m.)
Issued	18 years, 3 months ago (April 26, 2007)
Published	18 years, 3 months ago (April 26, 2007)
Published Online	18 years, 3 months ago (April 26, 2007)
Published Print	18 years, 3 months ago (May 15, 2007)

Funders 0

None

BibTeX

@article{Baillie_2007, title={Mapping binding sites for the PDE4D5 cAMP-specific phosphodiesterase to the N- and C-domains of β-arrestin using spot-immobilized peptide arrays}, volume={404}, ISSN={1470-8728}, url={http://dx.doi.org/10.1042/bj20070005}, DOI={10.1042/bj20070005}, number={1}, journal={Biochemical Journal}, publisher={Portland Press Ltd.}, author={Baillie, George S. and Adams, David R. and Bhari, Narinder and Houslay, Thomas M. and Vadrevu, Suryakiran and Meng, Dong and Li, Xiang and Dunlop, Allan and Milligan, Graeme and Bolger, Graeme B. and Klussmann, Enno and Houslay, Miles D.}, year={2007}, month=apr, pages={71–80} }

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  "abstract": "<jats:p>\u03b22-ARs (\u03b22-adrenoceptors) become desensitized rapidly upon recruitment of cytosolic \u03b2-arrestin. PDE4D5 (family 4 cAMP-specific phosphodiesterase, subfamily D, isoform 5) can be recruited in complex with \u03b2-arrestin, whereupon it regulates PKA (cAMP-dependent protein kinase) phosphorylation of the \u03b22-AR. In the present study, we have used novel technology, employing a library of overlapping peptides (25-mers) immobilized on cellulose membranes that scan the entire sequence of \u03b2-arrestin 2, to define the interaction sites on \u03b2-arrestin 2 for binding of PDE4D5 and the cognate long isoform, PDE4D3. We have identified a binding site in the \u03b2-arrestin 2 N-domain for the common PDE4D catalytic unit and two regions in the \u03b2-arrestin 2 C-domain that confer specificity for PDE4D5 binding. Alanine-scanning peptide array analysis of the N-domain binding region identified severely reduced interaction with PDE4D5 upon R26A substitution, and reduced interaction upon either K18A or T20A substitution. Similar analysis of the \u03b2-arrestin 2 C-domain identified Arg286 and Asp291, together with the Leu215\u2013His220 region, as being important for binding PDE4D5, but not PDE4D3. Transfection with wild-type \u03b2-arrestin 2 profoundly decreased isoprenaline-stimulated PKA phosphorylation of the \u03b22-AR in MEFs (mouse embryo fibroblasts) lacking both \u03b2-arrestin 1 and \u03b2-arrestin 2. This effect was negated using either the R26A or the R286A mutant form of \u03b2-arrestin 2 or a mutant with substitution of an alanine cassette for Leu215\u2013His220, which showed little or no PDE4D5 binding, but was still recruited to the \u03b22-AR upon isoprenaline challenge. These data show that the interaction of PDE4D5 with both the N- and C-domains of \u03b2-arrestin 2 are essential for \u03b22-AR regulation.</jats:p>",
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