Abstract:
:Protein kinases are key players in signal transduction pathways where they are crafted into two functional states. In response to growth factor binding stimulus, epidermal growth factor receptor (EGFR), which is physiologically populated in an autoinhibited inactive state, becomes active. Here, we outline a simple allostery scheme to clarify how an extracellular (ligand-dependent) binding event activates the intracellular EGFR kinase domain via (dimer-dependent) asymmetric dimerization, as well as how pathologically overexpressed EGFR or constitutively active mutants, leads to oncogenic pathway activation. Our underlying allosteric activation mechanism derives from a collection of inactive versus active EGFR structural, biochemical (negatively cooperative ligand binding), and biophysical (weak coupling between extracellular and intracellular kinase dimerization) data. The emerging structural insight reveals that ligand-dependent physiological activation is an outside-in allosteric activation with strong structural coupling across the membrane. In contrast, ligand-independent pathological activation is a weak inside-out activation mediated by intracellular kinase dimerization, which is structurally accommodated by additional extracellular dimers.
journal_name
Biophys Jjournal_title
Biophysical journalauthors
Tsai CJ,Nussinov Rdoi
10.1016/j.bpj.2019.05.021subject
Has Abstractpub_date
2019-07-09 00:00:00pages
5-13issue
1eissn
0006-3495issn
1542-0086pii
S0006-3495(19)30423-0journal_volume
117pub_type
杂志文章,评审abstract::A recently completed model of Ca concentration and movements in the cardiac cell diadic cleft space predicts that removal or neutralization of inner sarcolemmal (SL) leaflet anionic Ca-binding sites at the sarcolemmal border of this space will greatly diminish Na/Ca exchange-mediated Ca efflux. The present study tests...
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