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Binding, domain orientation, and dynamics of the lck SH3-SH2 domain pair and comparison with other Src-family kinases

Binding, domain orientation, and dynamics of the lck SH3-SH2 domain pair and comparison with other Src-family kinases
Binding, domain orientation, and dynamics of the lck SH3-SH2 domain pair and comparison with other Src-family kinases
The catalytic activity of Src-family kinases is regulated by association with its SH3 and SH2 domains. Activation requires displacement of intermolecular contacts by SH3/SH2 binding ligands resulting in dissociation of the SH3 and SH2 domains from the kinase domain. To understand the contribution of the SH3-SH2 domain pair to this regulatory process, the binding of peptides derived from physiologically relevant SH2 and SH3 interaction partners was studied for Lck and its relative Fyn by NMR spectroscopy. In contrast to Fyn, activating ligands do not induce communication between SH2 and SH3 domains in Lck. This can be attributed to the particular properties of the Lck SH3-SH2 linker which is shown to be extremely flexible thus effectively decoupling the behavior of the SH3 and SH2 domains. Measurements on the SH32 tandem from Lck further revealed a relative domain orientation that is distinctly different from that found in the Lck SH32 crystal structure and in other Src kinases. These data suggest that flexibility between SH2 and SH3 domains contributes to the adaptation of Src-family kinases to specific environments and distinct functions.
0006-2960
13043-13050
Hofmann, Gregor
7c9aa036-739e-46fd-81df-95fa300ccb6b
Schweimer, Kristian
4edb6631-b0d3-469b-bab7-aabbf871e038
Kiessling, Anke
7d023e0a-556b-42d5-913c-cb4c25396527
Hofinger, Edith
22cfc7fe-ee01-456b-b15c-a50b4f699775
Bauer, Finn
173a589d-b41e-463b-94a2-8d7aa7088177
Hoffmann, Silke
47d93559-8baa-468f-8cc2-b3cc3002f2da
Rösch, Paul
43fa376b-4559-4bc0-a700-ddb731dcdf9e
Campbell, Iain D.
54eba33e-94f7-450e-b555-c429dc2179de
Werner, Jörn M.
1b02513a-8310-4f4f-adac-dc2a466bd115
Sticht, Heinrich
0a9da836-cbd0-4993-9f15-2f0b30283567
Hofmann, Gregor
7c9aa036-739e-46fd-81df-95fa300ccb6b
Schweimer, Kristian
4edb6631-b0d3-469b-bab7-aabbf871e038
Kiessling, Anke
7d023e0a-556b-42d5-913c-cb4c25396527
Hofinger, Edith
22cfc7fe-ee01-456b-b15c-a50b4f699775
Bauer, Finn
173a589d-b41e-463b-94a2-8d7aa7088177
Hoffmann, Silke
47d93559-8baa-468f-8cc2-b3cc3002f2da
Rösch, Paul
43fa376b-4559-4bc0-a700-ddb731dcdf9e
Campbell, Iain D.
54eba33e-94f7-450e-b555-c429dc2179de
Werner, Jörn M.
1b02513a-8310-4f4f-adac-dc2a466bd115
Sticht, Heinrich
0a9da836-cbd0-4993-9f15-2f0b30283567

Hofmann, Gregor, Schweimer, Kristian, Kiessling, Anke, Hofinger, Edith, Bauer, Finn, Hoffmann, Silke, Rösch, Paul, Campbell, Iain D., Werner, Jörn M. and Sticht, Heinrich (2005) Binding, domain orientation, and dynamics of the lck SH3-SH2 domain pair and comparison with other Src-family kinases. Biochemistry, 44 (39), 13043-13050. (doi:10.1021/bi050814y).

Record type: Article

Abstract

The catalytic activity of Src-family kinases is regulated by association with its SH3 and SH2 domains. Activation requires displacement of intermolecular contacts by SH3/SH2 binding ligands resulting in dissociation of the SH3 and SH2 domains from the kinase domain. To understand the contribution of the SH3-SH2 domain pair to this regulatory process, the binding of peptides derived from physiologically relevant SH2 and SH3 interaction partners was studied for Lck and its relative Fyn by NMR spectroscopy. In contrast to Fyn, activating ligands do not induce communication between SH2 and SH3 domains in Lck. This can be attributed to the particular properties of the Lck SH3-SH2 linker which is shown to be extremely flexible thus effectively decoupling the behavior of the SH3 and SH2 domains. Measurements on the SH32 tandem from Lck further revealed a relative domain orientation that is distinctly different from that found in the Lck SH32 crystal structure and in other Src kinases. These data suggest that flexibility between SH2 and SH3 domains contributes to the adaptation of Src-family kinases to specific environments and distinct functions.

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Submitted date: 3 May 2003
Published date: 4 October 2005

Identifiers

Local EPrints ID: 56520
URI: https://eprints.soton.ac.uk/id/eprint/56520
ISSN: 0006-2960
PURE UUID: bca340a1-6aa4-4207-a888-a83d5f962ccc
ORCID for Jörn M. Werner: ORCID iD orcid.org/0000-0002-4712-1833

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Date deposited: 07 Aug 2008
Last modified: 06 Jun 2018 12:45

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Contributors

Author: Gregor Hofmann
Author: Kristian Schweimer
Author: Anke Kiessling
Author: Edith Hofinger
Author: Finn Bauer
Author: Silke Hoffmann
Author: Paul Rösch
Author: Iain D. Campbell
Author: Jörn M. Werner ORCID iD
Author: Heinrich Sticht

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