2WQE

Structure of S155R Aurora-A somatic mutant

Summary for 2WQE

• Entry DOI: 10.2210/pdb2wqe/pdb
• Related: 1MQ4 1MUO 1OL5 1OL6 1OL7 2BMC 2C6D 2C6E 2J4Z 2J50 2W1C 2W1D 2W1E 2W1F 2W1G
• Descriptor: SERINE/THREONINE-PROTEIN KINASE 6, ADENOSINE-5'-DIPHOSPHATE (3 entities in total)
• Functional Keywords: polymorphism, phosphoprotein, nucleotide-binding, cell cycle, transferase
• Biological source: HOMO SAPIENS
• Cellular location: Cytoplasm, cytoskeleton, centrosome: O14965
• Total number of polymer chains: 1
• Total formula weight: 31788.67

Authors

Bibby, R.,Bayliss, R. (deposition date: 2009-08-20, release date: 2009-09-29, Last modification date: 2023-12-20)

Primary citation

Bibby, R.A.,Tang, C.,Faisal, A.,Drosopoulos, K.,Lubbe, S.,Houlston, R.,Bayliss, R.,Linardopoulos, S.
A Cancer Associated Aurora-A Mutant is Mislocalised and Misregulated due to Loss of Interaction with Tpx2.
J.Biol.Chem., 284:33177-, 2009

PubMed Abstract: Mutations in protein kinases can drive cancer through alterations of the kinase activity or by uncoupling kinase activity from regulation. Changes to protein expression in Aurora A, a mitotic Ser/Thr kinase, are associated with the development of several human cancers, but the effects of somatic cancer-associated mutations have not been determined. In this study we show that Aurora A kinase activity is altered in different ways in three somatic cancer-associated mutations located within the catalytic domain; Aurora A(V174M) shows constitutively increased kinase activity, Aurora A(S155R) activity is decreased primarily due to misregulation, and Aurora A(S361*) activity is ablated due to loss of structural integrity. These alterations suggest vastly different mechanisms for the role of these three mutations in human cancer. We have further characterized the Aurora A(S155R) mutant protein, found that its reduced cellular activity and mislocalization are due to loss of interaction with TPX2, and deciphered the structural basis of the disruption at 2.5 A resolution. Previous studies have shown that disruption of the Aurora A/TPX2 interaction results in defective spindles that generate chromosomal abnormalities. In a panel of 40 samples from microsatellite instability-positive colon cancer patients, we found one example in which the tumor contained only Aurora A(S155R), whereas the normal tissue contained only wild-type Aurora A. We propose that the S155R mutation is an example of a somatic mutation associated with this tumor type, albeit at modest frequency, that could promote aneuploidy through the loss of regulated interactions between Aurora A and its protein partners.

PubMed: 19801554
DOI: 10.1074/JBC.M109.032722

Experimental method

X-RAY DIFFRACTION (2.5 Å)