L.D. Burtnick*, E.K. Koepf*, J.M. Grimes+, E.Y. Jones+, D.I. Stuart+, P. McLaughlin# and R.C. Robinson+
*Chemistry Dept., UBC, Vancouver, Canada, V6T 1Y6, #Edinburgh University, Edinburgh, U.K., EH8 9XD and +LMB, Oxford University, Oxford, U.K., OX1 3QU.
We present the structure of gelsolin, purified from horse blood plasma, as determined by x-ray crystallography to a resolution of 2.5 Å. Gelsolin comprises six structurally related domains that, in a Ca2+-free environment, pack together to form a compact globular structure in which the putative actin-binding sequences are not sufficiently exposed to enable binding to occur. However, we propose that binding Ca2+ can release the connections that join the N and C-terminal halves of gelsolin, enabling each half-gelsolin to bind actin relatively independently. Significant shifting among the domains in gelsolin may be accommodated by slack in linker strands of polypeptide that tie together the individual segments and does not require drastic alteration in the folding of any one particular domain. Such domain shifts in response to binding Ca2+ serve as bases for models of how gelsolin acts to sever, cap or nucleate F-actin filaments. The three dimensional model also invites renewed discussion of Ca2+-binding to segment 1 and polyphosphoinositide-binding to segment 2, and suggests how mutation at Asp-187 could initiate a series of events that lead to deposition of amyloid plaques, as observed in victims of familial amyloidosis (Finnish type).