title: Immunoglobulin VH clan and family identity predicts variable domain structure and may influence antigen binding.
abstract: Mammalian immunoglobulin VH families can be grouped into three distinct clans based upon sequence conservation in two of the three framework (FR) intervals. Through replacement/silent site substitution analysis, molecular modeling and mathematical evaluation of known immunoglobulin crystal structures, we demonstrate that this conservation reflects preservation of protein sequence and structure. Each clan contains a characteristic FR 1 interval that is solvent-exposed and structurally separated from the antigen binding site. Families within a clan contain their own unique FR 3 interval that is capable of either influencing the conformation of the antigen binding site or interacting directly with antigen. Our results provide a structural context for theories that address differential use of VH families in the immune response.
authors.affiliation: Division of Developmental and Clinical Immunology, University of Alabama, Birmingham 35294.
authors.forename: P M
authors.initials: PM
authors.lastname: Kirkham
authors.forename: F
authors.initials: F
authors.lastname: Mortari
authors.forename: J A
authors.initials: JA
authors.lastname: Newton
authors.forename: H W
authors.initials: HW
authors.lastname: Schroeder
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001666:Binding Sites, Antibody; D005312:Fetal Blood / Q000276:immunology; D015723:Gene Library; D005803:Genes, Immunoglobulin; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology; D008322:Mammals; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D011487:Protein Conformation; D012689:Sequence Homology, Nucleic Acid
chemical_list: D007140:Immunoglobulin Fab Fragments; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region