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Structure of the N-terminal half of gelsolin bound to actin: roles in severing, apoptosis and FAF

TitleStructure of the N-terminal half of gelsolin bound to actin: roles in severing, apoptosis and FAF
Publication TypeJournal Article
Year of Publication2004
AuthorsBurtnick, LD, Urosev, D, Irobi, E, Narayan, K, Robinson, RC
JournalEmbo Journal
Volume23
Pagination2713-2722
Date PublishedJul
Type of ArticleArticle
ISBN Number0261-4189
Keywords5-BISPHOSPHATE, actin, AMYLOIDOSIS-FINNISH TYPE, apoptosis, BINDING-SITE, CA2+ REGULATION, calcium, CRYSTAL-STRUCTURE, crystallographic structure, F-ACTIN, FAMILIAL AMYLOIDOSIS, FILAMENT BARBED ENDS, gelsolin, PHOSPHATIDYLINOSITOL 4, PLASMA GELSOLIN, X-RAY
Abstract

The actin filament-severing functionality of gelsolin resides in its N-terminal three domains (G1 - G3). We have determined the structure of this fragment in complex with an actin monomer. The structure reveals the dramatic domain rearrangements that activate G1 - G3, which include the replacement of interdomain interactions observed in the inactive, calcium-free protein by new contacts to actin, and by a novel G2 - G3 interface. Together, these conformational changes are critical for actin filament severing, and we suggest that their absence leads to the disease Finnish-type familial amyloidosis. Furthermore, we propose that association with actin drives the calcium-independent activation of isolated G1 G3 during apoptosis, and that a similar mechanism operates to activate native gelsolin at micromolar levels of calcium. This is the first structure of a filament-binding protein bound to actin and it sets stringent, high-resolution limitations on the arrangement of actin protomers within the filament.

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