ANALOGY AND SOLUTION SCATTERING MODELING - NEW STRUCTURAL STRATEGIES FOR THE MULTIDOMAIN PROTEINS OF COMPLEMENT, CARTILAGE AND THE IMMUNOGLOBULIN SUPERFAMILY

Many immunologically relevant proteins possess multidomain structures. Molecular structures both at the level of the individual domain and t hat of the intact protein are required for a full appreciation of func tion and control. Two recently developed structural approaches are rev iewed here. Analogy modelling methods are based on the current underst anding of many protein structures, and make possible the identificatio n of folds for superfamilies of unknown structures. An integrated mult idisciplinary predictive approach has been successfully applied to the von Willebrand factor type A, proteoglycan tandem repeat and factor I /membrane attack complex domains. The available experimental and predi ctive evidence is assembled in order to identify a known three-dimensi onal structure related to the unknown one of interest. Neutron and X-r ay scattering curve modelling provides information on the full multido main structure in solution. As scattering curves can be calculated fro m known atomic structures, the present availability of structures for many domains in conjunction with tight constraints based on these stru ctures and the covalent connections between them results in a small fa mily of allowed best-fit structures for a given scattering curve. The curve-fit procedure can be automated, and whole multidomain structures can be determined to a positional precision of the order of 0.2-1 nm. Such models are informative on the steric accessibility of each domai n and their functional activity, and this is illustrated for antibody, cell-surface and complement proteins.