FROM STRUCTURE TO FUNCTION OF PLASMA GELSOLIN. L.D. Burtnick*, E.K. Koepf*, J.M. Grimes+, E.Y. Jones+, D.I.H. Stuart+, P. McLaughlin# and R.C. Robinson+, *Chemistry Dept. UBC, Vancouver, Canada, V6T 1Z1, #Edinburgh University, Edinburgh, U.K., EH8 9XD and +LMB, Oxford University, Oxford, U.K., OX1 3QU.

The structure of horse plasma gelsolin to 2.5 Å resolution can be coupled with biochemical and biophysical results to explain the calcium-dependent severing of actin filaments by gelsolin. Gelsolin contains six similarly folded domains organized into two nearly independent halves. Connections between the halves are formed firstly by a long polypeptide loop that covalently links the terminus of S3 to the start of S4, and then by the C-terminal helical tail of the protein reaching back to lie parallel to a long helix in S2. We suggest that the binding of calcium to the second half of gelsolin releases the C-terminal tail from its interactions with S2. The two halves of the gelsolin molecule then can act relatively independently, restrained only by the 50 residue linker, to bind to actin units on opposite sides of an actin filament. We suggest that S2 binds first and positions S1 near to its binding site. The binding of S1 introduces sufficient steric conflict between S1/S3 and the next actin protomer in the filament to induce severing. These actions would be mirrored at an actin unit across the filament due to the binding of S4-S6, completing the severing and capping activity. Slack in the lengthy chains that link various of the domains of gelsolin would enable the required relative motions amongst the segments, without requiring significant changes in the secondary or tertiary structure of any individual domain.