Expression, intracellular distribution and basis for lack of catalytic activity of the PDE4A7 isoform encoded by the human PDE4A cAMP-specific phosphodiesterase gene

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dc.authorscopusid8591600600
dc.authorscopusid7004540505
dc.authorscopusid8764115500
dc.authorscopusid55420991400
dc.authorscopusid57198413811
dc.authorscopusid56372777000
dc.authorscopusid7004932551
dc.contributor.authorJohnston, Lee Ann
dc.contributor.authorErdogan, Suat
dc.contributor.authorCheung, York Fong
dc.contributor.authorSullivan, Michael
dc.contributor.authorBarber, Rachael
dc.contributor.authorLynch, Martin J.
dc.contributor.authorBaillie, George S.
dc.date.accessioned2024-09-19T15:45:24Z
dc.date.available2024-09-19T15:45:24Z
dc.date.issued2004
dc.departmentHatay Mustafa Kemal Üniversitesien_US
dc.description.abstractPDE4A7 is an isoform encoded by the human PDE4A cAMP-specific phosphodiesterase gene that fails to hydrolyse cAMP and whose transcripts are widely expressed. Removal of either the N-or C-terminal unique portions of PDE4A7 did not reconstitute catalytic activity, snowing that they did not exert a chronic inhibitory effect. A chimera (Hyb2), formed by swapping the unique N-terminal portion of PDE4A7 with that of the active PDE4A4C form, was not catalytically active. However, one formed (Hyb1) by swapping the unique C-terminal portion of PDE4A7 with that common to all active PDE4 isoforms was catalytically active. Compared with the active PDE4A4B isoform, Hyb1 exhibited a similar Km value for cAMP and IC50 value for rolipram inhibition, but was less sensitive to inhibition by Ro-20-1724 and denbufylline, and considerably more sensitive to thermal denaturation. The unique C-terminal region of PDE4A7 was unable to support an active catalytic unit, whereas its unique N-terrninal region can. The N-terminal portion of the PDE4 catalytic unit is essential for catalytic activity and can be supplied by either highly conserved sequence found in active PDE4 isoforms from all four PDE4 subfamilies or the unique N-terminal portion of PDE4A7. A discrete portion of the conserved C-terminal region in active PDE4A isoforms underpins their aberrant migration on SDS/PAGE. Unlike active PDE4A isoforms, PDE4A7 is exclusively localized to the P1 particulate fraction in cells. A region located within the C-terminal portion of active PDE4 isoforms prevents such exclusive targeting. Three functional regions in PDE4A isoforms are identified, which influence catalytic activity, subcellular targeting and conformational status.en_US
dc.identifier.doi10.1042/BJ20031662
dc.identifier.endpage384en_US
dc.identifier.issn0264-6021
dc.identifier.issue2en_US
dc.identifier.pmid15025561en_US
dc.identifier.scopus2-s2.0-2942724222en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage371en_US
dc.identifier.urihttps://doi.org/10.1042/BJ20031662
dc.identifier.urihttps://hdl.handle.net/20.500.12483/14650
dc.identifier.volume380en_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.relation.ispartofBiochemical Journalen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectcAMP-specific phosphodiesterase (PDE4A7)en_US
dc.subjectCatalytically inactive isoformen_US
dc.subjectIntracellular targetingen_US
dc.subjectPhosphodiesteraseen_US
dc.subjectRolipramen_US
dc.titleExpression, intracellular distribution and basis for lack of catalytic activity of the PDE4A7 isoform encoded by the human PDE4A cAMP-specific phosphodiesterase geneen_US
dc.typeArticleen_US

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