uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Helix Straightening as an Activation Mechanism in the Gelsolin Superfamily of Actin Regulatory Proteins
Department of Chemistry and Centre for Blood Research, Life Sciences Institute. (Leslie D. Burtnick)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. (Robert Robinson)
2009 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 284, no 32, 21265-21269 p.Article in journal (Refereed) Published
Abstract [en]

Villin and gelsolin consist of six homologous domains of the gelsolin/cofilin fold (V1-V6 and G1-G6, respectively). Villin differs   from gelsolin in possessing at its C terminus an unrelated seventh   domain, the villin headpiece. Here, we present the crystal structure of   villin domain V6 in an environment in which intact villin would be  inactive, in the absence of bound Ca2+ or phosphorylation. The structure of V6 more closely resembles that of the activated form of  G6, which contains one bound Ca2+, rather than that of the calcium   ion-free form of G6 within intact inactive gelsolin. Strikingly   apparent is that the long helix in V6 is straight, as found in the   activated form of G6, as opposed to the kinked version in inactive   gelsolin. Molecular dynamics calculations suggest that the preferable   conformation for this helix in the isolated G6 domain is also straight   in the absence of Ca2+ and other gelsolin domains. However, the G6   helix bends in intact calcium ion-free gelsolin to allow interaction   with G2 and G4. We suggest that a similar situation exists in villin.   Within the intact protein, a bent V6 helix, when triggered by Ca2+,   straightens and helps push apart adjacent domains to expose actin-binding sites within the protein. The sixth domain in this   superfamily of proteins serves as a keystone that locks together a compact ensemble of domains in an inactive state. Perturbing the   keystone initiates reorganization of the structure to reveal previously buried actin-binding sites.

Place, publisher, year, edition, pages
2009. Vol. 284, no 32, 21265-21269 p.
Keyword [en]
villin, gelsolin, actin, calcium activation
National Category
Medical and Health Sciences
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:uu:diva-89392DOI: 10.1074/jbc.M109.019760ISI: 000268564400020OAI: oai:DiVA.org:uu-89392DiVA: diva2:160257
Available from: 2009-02-12 Created: 2009-02-12 Last updated: 2010-07-12Bibliographically approved
In thesis
1. The Structural Basis of the Control of Actin Dynamics by the Gelsolin Superfamily Proteins
Open this publication in new window or tab >>The Structural Basis of the Control of Actin Dynamics by the Gelsolin Superfamily Proteins
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rearrangement of the actin cytoskeleton occurs in a variety of cellular processes and structures and involves a wide spectrum of proteins. Among these, the gelsolin superfamily proteins (GSPs) control actin organization by severing filaments, capping filament ends and bundling filaments. Structural changes within the GSPs are key in controling their functions. This thesis is aimed in understanding the activation mechanisms of the C-terminal halves of GSPs through investigating the atomic structures of gelsolin, adseverin and villin. X-ray crystallography was used to determine the structures of C-terminal fragments of these 3 proteins. The results demonstrate that: 1) The structure of the activated form of the C-terminal half of gelsolin displays an open conformation, with the actin-binding site on gelsolin domain 4 (G4) fully exposed and all three type-II calcium binding sites (CBS) occupied. Neither actin nor the type-I calcium, which is normally sandwiched between actin and G4, is required to achieve this conformation. 2) Calcium ions at both type-I and type-II CBSs of gelsolin were exchangable within the crystals. Extraction of calcium ions from the CBSs triggered local conformation changes which we speculate are the initial steps toward restoration of the arrangement of domains found in the calcium-free inactive form of gelsolin in solution. 3) The long helix of G6 in the calcium-bound structure is similar to the helix of calcium-free isolated villin domain 6 (V6). 4) The conformation of the C-terminal half of adseverin in the active state is similar to that of gelsolin. These results suggest that the C-terminal halves of GSPs are activated before forming a complex with actin. The activation involves straightening the helix of domain 6 which is a key component in the global conformation changes of C-terminal halves of these proteins. The results also suggest that a calcium ion may bind to the type-I CBS on domain 4 of the active conformation of GSPs concurrently with forming the complex with actin, hence, stabilizing the GSP:actin complex.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 37 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 425
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-89218 (URN)978-91-554-7428-7 (ISBN)
Public defence
2009-03-23, C10:305, Dept. of Medical Biochemistry and Microbiology, IMBIM, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2009-03-02 Created: 2009-02-09 Last updated: 2009-09-04Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Authority records BETA

Chumnarnsilpa, Sakesit

Search in DiVA

By author/editor
Chumnarnsilpa, Sakesit
By organisation
Department of Medical Biochemistry and Microbiology
In the same journal
Journal of Biological Chemistry
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 649 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf