Mutations of beta-arrestin 2 that limit self-association also interfere with interactions with the beta(2)-adrenoceptor and the ERK1/2 MAPKs: implications for beta(2)-adrenoceptor signalling via the ERK1/2 MAPKs.

Mutations of beta-arrestin 2 that limit self-association also interfere with interactions with the beta(2)-adrenoceptor and the ERK1/2 MAPKs: implications for beta(2)-adrenoceptor signalling via the ERK1/2 MAPKs. Research Abstract Details 

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Mutations of beta-arrestin 2 that limit self-association also interfere with interactions with the beta(2)-adrenoceptor and the ERK1/2 MAPKs: implications for beta(2)-adrenoceptor signalling via the ERK1/2 MAPKs. Abstract Text:

FRET (fluorescence resonance energy transfer) and co-immunoprecipitation studies confirmed the capacity of beta-arrestin 2 to self-associate. Amino acids potentially involved in direct protein-protein interaction were identified via combinations of spot-immobilized peptide arrays and mapping of surface exposure. Among potential key amino acids, Lys(285), Arg(286) and Lys(295) are part of a continuous surface epitope located in the polar core between the N- and C-terminal domains. Introduction of K285A/R286A mutations into beta-arrestin 2-eCFP (where eCFP is enhanced cyan fluorescent protein) and beta-arrestin 2-eYFP (where eYFP is enhanced yellow fluorescent protein) constructs substantially reduced FRET, whereas introduction of a K295A mutation had a more limited effect. Neither of these mutants was able to promote beta(2)-adrenoceptor-mediated phosphorylation of the ERK1/2 (extracellular-signal-regulated kinase 1/2) MAPKs (mitogen-activated protein kinases). Both beta-arrestin 2 mutants displayed limited capacity to co-immunoprecipitate ERK1/2 and further spot-immobilized peptide arrays indicated each of Lys(285), Arg(286) and particularly Lys(295) to be important for this interaction. Direct interactions between beta-arrestin 2 and the beta(2)-adrenoceptor were also compromised by both K285A/R286A and K295A mutations of beta-arrestin 2. These were not non-specific effects linked to improper folding of beta-arrestin 2 as limited proteolysis was unable to distinguish the K285A/R286A or K295A mutants from wild-type beta-arrestin 2, and the interaction of beta-arrestin 2 with JNK3 (c-Jun N-terminal kinase 3) was unaffected by the K285A/R286A or L295A mutations. These results suggest that amino acids important for self-association of beta-arrestin 2 also play an important role in the interaction with both the beta(2)-adrenoceptor and the ERK1/2 MAPKs. Regulation of beta-arrestin 2 self-association may therefore control beta-arrestin 2-mediated beta(2)-adrenoceptor-ERK1/2 MAPK signalling.

Mutations of beta-arrestin 2 that limit self-association also interfere with interactions with the beta(2)-adrenoceptor and the ERK1/2 MAPKs: implications for beta(2)-adrenoceptor signalling via the ERK1/2 MAPKs. Publishing Authors By Initials

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Mutations of beta-arrestin 2 that limit self-association also interfere with interactions with the beta(2)-adrenoceptor and the ERK1/2 MAPKs: implications for beta(2)-adrenoceptor signalling via the ERK1/2 MAPKs. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: The Biochemical journal

VOLUME: 413

Page Numbers: 51-60

Journal Abbreviation: Biochem. J.

ISSN: 1470-8728

DAY: 1

MONTH: Jul

YEAR: 2008

Mutations of beta-arrestin 2 that limit self-association also interfere with interactions with the beta(2)-adrenoceptor and the ERK1/2 MAPKs: implications for beta(2)-adrenoceptor signalling via the ERK1/2 MAPKs. Information

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LANGUAGE: eng

NlmUniqueID: 2984726

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Grant and Affiliation Information for Mutations of beta-arrestin 2 that limit self-association also interfere with interactions with the beta(2)-adrenoceptor and the ERK1/2 MAPKs: implications for beta(2)-adrenoceptor signalling via the ERK1/2 MAPKs.

AFFILIATION: Sir Henry Welcome Functional Genomics Facility, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, U.K.

Country: England

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MEDLINETA: Biochem J

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