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The structure of gelsolin bound to ATP.
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
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2006 (English)In: J Mol Biol, ISSN 0022-2836, Vol. 357, no 3, 765-72 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2006. Vol. 357, no 3, 765-72 p.
Identifiers
URN: urn:nbn:se:uu:diva-80386PubMedID: 16469333OAI: oai:DiVA.org:uu-80386DiVA: diva2:108300
Available from: 2006-05-08 Created: 2006-05-08 Last updated: 2011-01-11
In thesis
1. Structural and Functional Studies of Gelsolin Family Proteins
Open this publication in new window or tab >>Structural and Functional Studies of Gelsolin Family Proteins
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The actin cytoskeleton is a complex structure that performs a wide range of cellular functions including: cell locomotion, cytokinesis, chemotaxis, signal transduction and apoptosis. The coordinated assembly and disassembly of actin filaments is controlled by a multitude of proteins (ABPs) in the cell. There are over 160 actin-binding proteins known, which with actin, account for approximately 25% of cellular protein. ABPs are classified to several major groups based on their sequence identity and functions.

In this work, we have elucidated the crystal structure of ATP bound gelsolin. We have shown that ATP binding involves the two halves of gelsolin through forming numerous polar and hydrophobic contacts. Amino acid residues that form the ATP-binding sites in inactive gelsolin are widely dispersed in the activated molecule, and hence, ATP binding is disrupted on gelsolin activation. This suggests that binding of ATP may modulate the sensitivity of gelsolin to calcium ions.

The structure of human gelsolin domains 1-3 bound to actin revealed a calcium ion bound to domain 2. Here, we demonstrated that only two calcium ions are needed to activate geloslin. We speculate that this domain 2 calcium ion and the one in domain 6 participate in the initial activation of gelsolin.

The crystal structure of the activated adseverin C-terminus is highly similar to that of the C-terminus of gelsolin. Comparative analysis suggests that, like the gelsolin C-terminus, adseverin will also contact actin through domain 4 and domain 6. Biochemical experiments, presented here, show that a minimum of one calcium is required for adseverin to depolymerizing actin filaments compared to two calcium for gelsolin. We speculate that this is due to the lack of the C-terminal extension in adseverin.

We undertook a comparative analysis of four members of the gelsolin family proteins, gelsolin, adseverin, villin and capG, in the aspects of their calcium binding, pH activation and ATP binding. The results show that only gelsolin and adseverin are able to depolymerize actin filaments at pH < 6 in the absence of calcium ions and only gelsolin bind to ATP.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 41 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 427
National Category
Structural Biology
Identifiers
urn:nbn:se:uu:diva-98226 (URN)978-91-554-7434-8 (ISBN)
Public defence
2009-03-25, C10:301, Uppsala Biomedical Center (BMC), Husargatan 3, Uppsala, 09:15 (English)
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Available from: 2009-03-02 Created: 2009-02-18 Last updated: 2010-01-13Bibliographically approved

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Ma, Qing

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