Analogy and solution scattering modelling: 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 that of the intact protein are required for a full appreciation of function and control. Two recently developed structural approaches are reviewed here. Analogy modelling methods are based on the current understanding of many protein structures, and make possible the identification of folds for superfamilies of unknown structures. An integrated multidisciplinary 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 predictive evidence is assembled in order to identify a known three-dimensional structure related to the unknown one of interest. Neutron and X-ray scattering curve modelling provides information on the full multidomain structure in solution. As scattering curves can be calculated from known atomic structures, the present availability of structures for many domains in conjunction with tight constraints based on these structures and the covalent connections between them results in a small family 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 domain and their functional activity, and this is illustrated for antibody, cell-surface and complement proteins.
Department of Biochemistry and Molecular Biology, Royal Free Hospital School of Medicine, London, UK. steve@rfhsm.ac.uk
S J
SJ
Perkins
C G
CG
Ullman
N C
NC
Brissett
D
D
Chamberlain
M K
MK
Boehm
D000818:Animals; D000906:Antibodies / Q000737:chemistry; D002356:Cartilage; D003165:Complement System Proteins / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry*; D008565:Membrane Proteins / Q000737:chemistry; D008958:Models, Molecular; D009502:Neutrons; D017510:Protein Folding; D012542:Scattering, Radiation; D012996:Solutions
D000906:Antibodies; D007136:Immunoglobulins; D008565:Membrane Proteins; D012996:Solutions; D003165:Complement System Proteins