Binding of TPX2 to Aurora A Alters Substrate and Inhibitor Interactions

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• 作者：Kelly Anderson ; Jingsong Yang ; Kristin Koretke ; Kelvin Nurse ; Amy Calamari ; Robert B. Kirkpatrick ; Denis Patrick ; Domingos Silva ; Peter J. Tummino ; Robert A. Copeland ; Zhihong Lai
• 刊名：Biochemistry
• 出版年：2007
• 出版时间：September 11, 2007
• 年：2007
• 卷：46
• 期：36
• 页码：10287 - 10295
• 全文大小：269K
• 年卷期：v.46,no.36(September 11, 2007)
• ISSN：1520-4995

文摘

The Aurora kinases are a family of serine/threonine kinases involved in mitosis. The expressionof AurA is ubiquitous and cell cycle regulated. It is overexpressed in many tumor types, including breast,colon, and ovarian. TPX2 is a binding partner and activator of AurA. A fragment of TPX2 (residues1-43) has been shown to be sufficient for binding, kinase activation, and protection from dephosphorylation.We have shown that the addition of TPX2(1-43) increases the catalytic efficiency of AurA. While TPX2binding has no effect on the turnover number of AurA and does not change the reaction mechanism(characterized here to be a rapid equilibrium random mechanism), it increases the binding affinity of bothATP and a peptide substrate. We have also demonstrated differences in the inhibitor structure-activityrelationship (SAR) in the presence or absence of TPX2(1-43). To better understand the differential SAR,we carried out computer modeling studies to gain insight into the effect of TPX2 on the binding interactionsbetween AurA and inhibitors. Our working hypothesis is that TPX2 binding decreases the size andaccessibility of a hydrophobic pocket, adjacent to the ATP site, to inhibitors.