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Structural studies of proteins in apoptosis and lipid signaling
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Responsible organisation
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Signaling pathways control the fate of the cell. For example, they promote cell survival or commit the cell to death (apoptosis) in response to cell injury or developmental stimuli, decisions, which are vital for the proper development and functioning of metazoan. Tight control of such pathways is essential; dysregulation of apoptosis can disrupt the delicate balance between cell proliferation and cell death ending up in pathological processes, including cancer, autoimmunity diseases, inflammatory diseases, or degenerative disorders. We have used a structural genomic approach to study the structure and function of key proteins involved in apoptosis and lipid signaling: the antiapoptotic Bcl-2 family member Bfl-1 in complex with a Bim peptide, the BIR domains of the Inhibitor of Apoptosis (IAP) family members, cIAP2 and NAIP and the a lipid kinase YegS. The structural analysis of the apoptosis regulatory proteins has revealed important information on the structural determinants for recognition of interacting proteins, which can now assist in the development of therapeutic drugs for human diseases. The structural and complementing biochemical studies of the lipid kinase YegS have reveled the first detailed information on a lipid kinase and explained important aspects of its structure-function relationship.

Finally, one subject of this work aim to solve what is arguably the most challenging problem in structural projects – to obtain a high production level of proteins suitable for structural studies. We have developed a highthroughput protein solubility screening, the colony filtration (CoFi) blot, which allows soluble clones to be identified from large libraries of protein variants and now constitute a powerful tool for solving difficult protein production problems.

Place, publisher, year, edition, pages
Stockholm: Institutionen för biokemi och biofysik , 2008. , 74 p.
Keyword [en]
proteins, crystal structure, apoptosis, cancer, CoFi-Blot, kinases, lipid signaling
National Category
Structural Biology
Research subject
Structural Biology
Identifiers
URN: urn:nbn:se:su:diva-8212ISBN: 978-91-7155-703-2 (print)OAI: oai:DiVA.org:su-8212DiVA: diva2:199820
Public defence
2008-09-11, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8 C, Stockholm, 10:00 (English)
Opponent
Supervisors
Available from: 2008-09-22 Created: 2008-09-22 Last updated: 2010-01-13Bibliographically approved
List of papers
1. Completing the family portrait of the anti-apoptotic Bcl-2 proteins: Crystal structure of human Bfl-1 in complex with Bim
Open this publication in new window or tab >>Completing the family portrait of the anti-apoptotic Bcl-2 proteins: Crystal structure of human Bfl-1 in complex with Bim
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2008 (English)In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 582, no 25-26, 3590-3594 p.Article in journal (Refereed) Published
Abstract [en]

Evasion of apoptosis is recognized as a characteristic of malignant growth. Anti-apoptotic B-cell lymphoma-2 (Bcl-2) family members have therefore emerged as potential therapeutic targets due to their critical role in proliferating cancer cells. Here, we present the crystal structure of Bfl-1, the last anti-apoptotic Bcl-2 family member to be structurally characterized, in complex with a peptide corresponding to the BH3 region of the pro-apoptotic protein Bim. The structure reveals distinct features at the peptide-binding site, likely to define the binding specificity for pro-apoptotic proteins. Superposition of the Bfl-1:Bim complex with that of Mcl-1:Bim reveals a significant local plasticity of hydrophobic interactions contributed by the Bim peptide, likely to be the basis for the multi specificity of Bim for anti-apoptotic proteins.

Keyword
Apoptosis, B-cell lymphoma-2, Cancer, Bfl-1; A1, Crystal structure
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-25483 (URN)10.1016/j.febslet.2008.09.028 (DOI)000260807500004 ()
Available from: 2008-09-22 Created: 2008-09-22 Last updated: 2012-02-13Bibliographically approved
2. The first crystal structure of BIR domains from Human NAIP and cIAP
Open this publication in new window or tab >>The first crystal structure of BIR domains from Human NAIP and cIAP
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Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:su:diva-25484 (URN)
Note
Part of urn:nbn:se:su:diva-8212Available from: 2008-09-22 Created: 2008-09-22Bibliographically approved
3. 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
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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: 2011-02-11Bibliographically approved
4. Colony filtration blot: a new screening method for soluble protein expression in Escherichia coli
Open this publication in new window or tab >>Colony filtration blot: a new screening method for soluble protein expression in Escherichia coli
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2005 (English)In: Nature Methods, ISSN 1548-7091, Vol. 2, no 7, 507-509 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-25545 (URN)
Note
Part of urn:nbn:se:su:diva-8261Available from: 2008-10-23 Created: 2008-10-14 Last updated: 2010-01-13Bibliographically approved

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