STRUCTURE-FUNCTION CORRELATIONS OF CALCIUM-BINDING AND CALCIUM-CHANNEL ACTIVITIES BASED ON 3-DIMENSIONAL MODELS OF HUMAN ANNEXIN-I, ANNEXIN-II, ANNEXIN-III, ANNEXIN-V AND ANNEXIN-VII

The annexins are a family of calcium-dependent phospholipid-binding pr oteins which share a high degree of primary sequence similarity. Using a model of the crystal structure of annexin V as a template, 3-dimens ional models of human annexins I, II, III and VII were constructed by homology modeling (J. Greer, J MoL Biol. 153,1027-1042,198 1; J.M. Che n, G. Lee, R.B. Murphy, R.P. Carty, P.W. Brant-Rauf, E. Friedman and M .R. Pincus, J Biomolec. Str. Dyn. 6,859-87,1989) for the 316 amino aci d portions corresponding to the annexin V structure published by Huber et al. (J. Mol. Biol. 223,683-704,1992). These methods were used to s tudy structure-function correlations for calcium ion binding and calci um channel activity. Published experimental data are specifically show n to be consistent with the annexin models. Possible intramolecular di sulfide bridges were identified in annexin I (between Cys297 and Cys31 6) and in annexins 11 and VII (between Cys115 and Cys243). Each of the annexin models have 3 postulated calcium binding sites, usually via a Gly-Xxx-Gly-Thr loop with an acidic Glu or Asp residue 42 positions C -terminal to the first Gly. Despite a nonconserved binding site sequen ce, annexins I and II are able to coordinate calcium in domain 3 since the residue in the second loop position is directed toward the solven t away from the binding pocket. This finding also suggests a mechanism for a conformational change upon binding calcium. Highly conserved Ar g and acidic sidechains stabilize the channel pore structure; annexin channels probably exist in a closed state normally. Arg271 may be invo lved in channel opening upon activation: basic residue 254 can stabili ze Glu112, which allows Arg271 to interact with residue 95 instead of Glu112. Residue 267, found on the convex surface at the pore opening, may also be important in modifying channel activity.