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Protein Science (2006), 15:2402-2410. Published by Cold Spring Harbor Laboratory Press. Copyright © 2006 The Protein Society
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Altered dynamics in Lck SH3 upon binding to the LBD1 domain of Herpesvirus saimiri Tip

David D. Weis1, Peter Kjellen2,3, Bartholomew M. Sefton2 and John R. Engen1,4

1 Department of Chemistry, University of New Mexico, Albuquerque, New Mexico 87131, USA
2 Molecular Cell and Biology Laboratory, The Salk Institute, La Jolla, California 92037, USA

(RECEIVED December 6, 2005; FINAL REVISION June 4, 2006; ACCEPTED July 18, 2006)

The Tip protein from Herpesvirus saimiri interacts with the SH3 domain from the Src-family kinase Lck via a proline-containing sequence termed LBD1. Src-family kinase SH3 domains related to Lck have been shown to be dynamic in solution and partially unfold under physiological conditions. The rate of such partial unfolding is reduced by viral protein binding. To determine if the Lck SH3 domain displayed similar behavior, the domain was investigated with hydrogen exchange and mass spectrometry. Lck SH3 was found to be highly dynamic in solution. While other SH3 domains require as much as 10,000 sec to become totally deuterated, Lck SH3 became almost completely labeled within 200 sec. A partial unfolding event involving 8–10 residues was observed with a half-life of ~10 sec. Tip LBD1 binding did not cause gross structural changes in Lck SH3 but globally stabilized the domain and reduced the rate of partial unfolding by a factor of five. The region of partial unfolding in Lck SH3 was found to be similar to that identified for other SH3 domains that partially unfold. Although the sequence conservation between Lck SH3 and other closely related SH3 domains is high, the dynamics do not appear to be conserved.

Keywords: hydrogen exchange; mass spectrometry; Src-family kinase; EX1 kinetics; protein unfolding


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