Please use this identifier to cite or link to this item: http://hdl.handle.net/2067/49431
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dc.contributor.authorOlivieri, Cristinait
dc.contributor.authorWalker, Caitlinit
dc.contributor.authorManu, V Sit
dc.contributor.authorPorcelli, Fernandoit
dc.contributor.authorTaylor, Susan Sit
dc.contributor.authorBernlohr, David Ait
dc.contributor.authorVeglia, Gianluigiit
dc.date.accessioned2023-03-30T15:46:43Z-
dc.date.available2023-03-30T15:46:43Z-
dc.date.issued2023it
dc.identifier.issn00145793, 18733468it
dc.identifier.urihttp://hdl.handle.net/2067/49431-
dc.description.abstractThe cAMP-dependent protein kinase A (PKA) is the archetypical eukaryotic kinase. The catalytic subunit (PKA-C) structure is highly conserved among the AGC-kinase family. PKA-C is a bilobal enzyme with a dynamic N-lobe, harboring the ATP binding site and a more rigid helical C-lobe. The substrate-binding groove resides at the interface of the two lobes. A distinct feature of PKA-C is the positive binding cooperativity between nucleotide and substrate. Several PKA-C mutations lead to the development of adenocarcinomas, myxomas, and other rare forms of liver tumors. NMR spectroscopy shows that these mutations disrupt the allosteric communication between the two lobes, causing a drastic decrease in binding cooperativity. The loss of cooperativity correlates with changes in substrate fidelity and reduced kinase affinity for the endogenous inhibitor PKI. The similarity between PKI and the inhibitory sequence of the kinase regulatory subunits suggests that the overall mechanism of regulation of the kinase may be disrupted. We surmise that a reduced or obliterated cooperativity may constitute a common trait for both orthosteric and allosteric mutations of PKA-C that may lead to dysregulation and disease.it
dc.language.isoengit
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.titleAn NMR portrait of functional and dysfunctional allosteric cooperativity in cAMP-dependent protein kinase Ait
dc.typearticle*
dc.identifier.doi10.1002/1873-3468.14610it
dc.identifier.pmid36892429it
dc.identifier.scopus2-s2.0-85150957456it
dc.identifier.urlhttps://febs.onlinelibrary.wiley.com/toc/18733468/2023/597/6it
dc.relation.journalFEBS LETTERSit
dc.description.internationalit
dc.contributor.countryITAit
dc.contributor.countryUSAit
dc.type.refereeREF_1it
dc.type.miur262*
item.fulltextWith Fulltext-
item.openairetypearticle-
item.cerifentitytypePublications-
item.grantfulltextrestricted-
item.languageiso639-1en-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
crisitem.journal.journalissn0014-5793-
crisitem.journal.anceE063114-
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