Structure of the N-terminal half of gelsolin bound to actin: roles in severing, apoptosis and FAF.
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.
Burtnick
Leslie D
LD
Department of Chemistry and Centre for Blood Research, The University of British Columbia, Vancouver, BC, Canada.
Urosev
Dunja
D
Irobi
Edward
E
Narayan
Kartik
K
Robinson
Robert C
RC
D000199:Actins / Q000737:chemistry / Q000378:metabolism*; D028226:Amyloidosis, Familial / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D018360:Crystallography, X-Ray; D018260:Gelsolin / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D006736:Horses; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
D000199:Actins; D018260:Gelsolin; D002118:Calcium