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Structural studies of three cell signaling proteins: crystal structures of EphB1, PTPA, and YegS
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Kinases and phosphatases are key regulatory proteins in the cell. The disruption of their activities leads ultimately to the abolishment of the homeostasis of the cell, and is frequently correlated with cancer. EphB1 is a member of the largest family of receptor tyrosine kinases. It is associated with neurogenesis, angiogenesis, and cancer. The cytosolic part of the human EphB1 receptor is composed of two domains. Successful generation of soluble constructs, using a novel random construct screening approach, led to the structure determination of the kinase domain of this receptor. The native structure and the complex structure with an ATP analogue revealed novel features in the regulation of the Eph family of kinases.

The structure of PTPA, an activator of protein phosphatase 2 A, a tumor suppressor and a key phosphatase in the cell was solved. The structure revealed a novel fold containing a conserved cleft predicted to be involved in interaction with PP2A.

Finally, the structure of YegS, an Escherichia coli protein annotated as a putative diacylglycerol kinase, has been determined. Beside the elucidation of its atomic structure, a phosphatidylglycerol (PG) kinase activity, never seen before, has been assigned to YegS based on biochemical studies. The YegS structure shows resemblance to the fold previously seen in NAD kinases. The structure also revealed the existence of a novel metal site that could potentially play a regulatory role. The YegS structure has important implications for understanding related proteins in pathogenic organisms and is the first homologue of a human lipid kinase for which the structure has been elucidated.

Place, publisher, year, edition, pages
Stockholm: Institutionen för biokemi och biofysik , 2007. , 74 p.
Keyword [en]
protein production, structural genomics, cell signaling
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:su:diva-6577ISBN: 91-7155-364-9 (print)OAI: oai:DiVA.org:su-6577DiVA: diva2:196679
Public defence
2007-02-23, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 09:30
Opponent
Supervisors
Available from: 2007-02-01 Created: 2007-02-01 Last updated: 2011-02-11Bibliographically approved
List of papers
1. Expression and phosphorylation studies of the cytosolic domain of the EphB1 receptor
Open this publication in new window or tab >>Expression and phosphorylation studies of the cytosolic domain of the EphB1 receptor
Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-24062 (URN)
Note
Part of urn:nbn:se:su:diva-6577Available from: 2007-02-01 Created: 2007-02-01 Last updated: 2010-01-13Bibliographically approved
2. Crystal structure of the kinase domain of the human EphB1
Open this publication in new window or tab >>Crystal structure of the kinase domain of the human EphB1
Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-24063 (URN)
Note
Part of urn:nbn:se:su:diva-6577Available from: 2007-02-01 Created: 2007-02-01 Last updated: 2010-01-13Bibliographically approved
3. The crystal structure of a human PP2A phosphatase activator reveals a novel fold and highly conserved cleft implicated in protein-protein interactions
Open this publication in new window or tab >>The crystal structure of a human PP2A phosphatase activator reveals a novel fold and highly conserved cleft implicated in protein-protein interactions
Show others...
2006 In: Journal of Biological Chemistry, ISSN 0021-9258, Vol. 281, no 32, 22434-22438 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-24064 (URN)
Note
Part of urn:nbn:se:su:diva-6577Available from: 2007-02-01 Created: 2007-02-01Bibliographically approved
4. Expression, purification, crystallization and preliminary diffraction studies of the mammalian DAG kinase homologue YegS from Escherichia coli
Open this publication in new window or tab >>Expression, purification, crystallization and preliminary diffraction studies of the mammalian DAG kinase homologue YegS from Escherichia coli
2006 In: Acta crystallographica series F, ISSN 1744-3091, Vol. 62, no 3, 295-297 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-24065 (URN)
Note
Part of urn:nbn:se:su:diva-6577Available from: 2007-02-01 Created: 2007-02-01Bibliographically approved
5. Crystal structure of YegS, a homologue to the mammalian diacylglycerol kinases, reveals a novel regulatory metal binding site
Open this publication in new window or tab >>Crystal structure of YegS, a homologue to the mammalian diacylglycerol kinases, reveals a novel regulatory metal binding site
Show others...
2007 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 282, no 27, 19644-19652 p.Article in journal (Refereed) Published
Abstract [en]

The human lipid kinase family controls cell proliferation, differentiation, and tumorigenesis and includes diacylglycerol kinases, sphingosine kinases, and ceramide kinases. YegS is an Escherichia coli protein with significant sequence homology to the catalytic domain of the human lipid kinases. We have solved the crystal structure of YegS and shown that it is a lipid kinase with phosphatidylglycerol kinase activity. The crystal structure reveals a two-domain protein with significant structural similarity to a family of NAD kinases. The active site is located in the interdomain cleft formed by four conserved sequence motifs. Surprisingly, the structure reveals a novel metal binding site composed of residues conserved in most lipid kinases.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:su:diva-25485 (URN)10.1074/jbc.M604852200 (DOI)000247650600039 ()
Available from: 2008-09-22 Created: 2008-09-22 Last updated: 2017-12-13Bibliographically approved
6. A high throughput method for the detection of metalloproteins on a microgram scale
Open this publication in new window or tab >>A high throughput method for the detection of metalloproteins on a microgram scale
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2005 In: Molecular & cellular proteomics, ISSN 1535-9476, Vol. 4, no 6, 827-834 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-24067 (URN)
Note
Part of urn:nbn:se:su:diva-6577Available from: 2007-02-01 Created: 2007-02-01Bibliographically approved
7. C1-Tetrahydrofolate synthase stabilizes HIF-1a by disrupting the interaction with the von Hippel Lindau tumor suppressor gene product
Open this publication in new window or tab >>C1-Tetrahydrofolate synthase stabilizes HIF-1a by disrupting the interaction with the von Hippel Lindau tumor suppressor gene product
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Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-24068 (URN)
Note
Part of urn:nbn:se:su:diva-6577Available from: 2007-02-01 Created: 2007-02-01 Last updated: 2010-01-13Bibliographically approved

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