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dc.contributor.authorMirza, Amar
dc.date.accessioned2014-03-04T18:25:00Z
dc.date.available2014-03-04T18:25:00Z
dc.date.issued2009-12
dc.identifier.othermirza_amar_200912_bs
dc.identifier.urihttp://purl.galileo.usg.edu/uga_etd/mirza_amar_200912_bs
dc.identifier.urihttp://hdl.handle.net/10724/26107
dc.description.abstractThe Epidermal Growth Factor Receptor (EGFR) and related ErbB kinases have functionally diverged from other receptor and non-receptor tyrosine kinases to be activated by a unique allosteric mechanism, in which two kinase domains activate each other through coordinated interactions between the catalytic core and the flanking juxtamembrane (JM) and COOH-terminal tail (C-terminal tail) segments. To identify key residues that contribute to the functional divergence of the ErbB family, a Bayseian approach was used to infer the selective constraints distinguishing ErbB from non-ErbB tyrosine kinases. Strong ErbB-specific constraints are imposed on residues that tether the JM and C-terminal tail segments to key functional regions of the kinase core. The strongest constraint is imposed on a glutamine (Q791), which tethers the C-terminal tail to a conserved inter-lobe salt bridge that is critical for inter-lobe movement. The malleability of this inter-lobe tether in the open and closed states of EGFR suggests a mechanism by which inter-lobe movement and ATP binding can be coordinated with conformational changes in the C-terminal tail. Likewise, an ErbB specific [YL]xx[AG] motif in the C-helix appears to play an active role in coupling JM and C-helix movement. We propose that the JM and C-terminal tail segments flanking the ErbB kinase core are cis elements that that have co-evolved with the kinase core to tightly regulate activity. Such a view readily explains the activating and inhibitory roles of the JM and C-terminal tail segments in EGFR functions, and provides new hypotheses for experimental studies.
dc.languageeng
dc.publisheruga
dc.rightspublic
dc.subjectEpidermal Growth Factor Receptor
dc.subjectC-Terminal Tail
dc.subjectevolution
dc.subjectCHAIN Program
dc.subjectCis regulation
dc.subjectJuxtamembrane region
dc.titleAnalysis of the evolutionary constraints distinguishing ErbB tyrosine kinases suggests a cis regulatory function for the Juxtamembrane and COOH-terminal tail segments
dc.typeHonors
dc.description.degreeBS
dc.description.departmentBiochemistry and Molecular Biology
dc.description.majorBiochemistry and Molecular Biology
dc.description.advisorNatarajan Kannan
dc.description.committeeNatarajan Kannan
dc.description.committeeMorad Mustafa


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