The crystal structure of the C-terminus of adseverin reveals the actin-binding interface

Sakesit Chumnarnsilpa, Lin Lee Wei, Shalini Nag, Balakrishnan Kannan, Mårten Larsson, Leslie D. Burtnick, Robert C. Robinson

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23 Citations (Scopus)

Abstract

Adseverin is a member of the calcium-regulated gelsolin superfamily of actin severing and capping proteins. Adseverin comprises 6 homologous domains (A1-A6), which share 60% identity with the 6 domains from gelsolin (G1-G6). Adseverin is truncated in comparison to gelsolin, lacking the C-terminal extension that masks the F-actin binding site in calcium-free gelsolin. Biochemical assays have indicated differences in the interaction of the C-terminal halves of adseverin and gelsolin with actin. Gelsolin contacts actin through a major site on G4 and a minor site on G6, whereas adseverin uses a site on A5. Here, we present the X-ray structure of the activated C-terminal half of adseverin (A4-A6). This structure is highly similar to that of the activated form of the C-terminal half of gelsolin (G4-G6), both in arrangement of domains and in the 3 bound calcium ions. Comparative analysis of the actin-binding surfaces observed in the G4-G6/actin structure suggests that adseverin in this conformation will also be able to interact with actin through A4 and A6, whereas the A5 surface is obscured. A single residue mutation in A4-A6 located at the predicted A4/actin interface completely abrogates actin sequestration. A model of calcium-free adseverin, constructed from the structure of gelsolin, predicts that in the absence of a gelsolin-like C-terminal extension the interaction between A2 and A6 provides the steric inhibition to prevent interaction with F-actin. We propose that calcium binding to the N terminus of adseverin dominates the activation process to expose the F-actin binding site on A2.

Original languageEnglish
Pages (from-to)13719-13724
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number33
DOIs
Publication statusPublished - Aug 18 2009

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Keywords

  • Calcium activated
  • Gelsolin
  • TIRF

ASJC Scopus subject areas

  • General

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