Analysis of the evolutionary constraints distinguishing ErbB tyrosine kinases suggests a cis regulatory function for the Juxtamembrane and COOH-terminal tail segments
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The 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.