title: Protein-protein interactions in crystals of the human receptor-type protein tyrosine phosphatase ICA512 ectodomain.
abstract: ICA512 (or IA-2) is a transmembrane protein-tyrosine phosphatase located in secretory granules of neuroendocrine cells. Initially, it was identified as one of the main antigens of autoimmune diabetes. Later, it was found that during insulin secretion, the cytoplasmic domain of ICA512 is cleaved and relocated to the nucleus, where it stimulates the transcription of the insulin gene. The role of the other parts of the receptor in insulin secretion is yet to be unveiled. The structures of the intracellular pseudocatalytic and mature extracellular domains are known, but the transmembrane domain and several intracellular and extracellular parts of the receptor are poorly characterized. Moreover the overall structure of the receptor remains to be established. We started to address this issue studying by X-ray crystallography the structure of the mature ectodomain of ICA512 (ME ICA512) and variants thereof. The variants and crystallization conditions were chosen with the purpose of exploring putative association interfaces, metal binding sites and all other structural details that might help, in subsequent works, to build a model of the entire receptor. Several structural features were clarified and three main different association modes of ME ICA512 were identified. The results provide essential pieces of information for the design of new experiments aimed to assess the structure in vivo.
authors.affiliation: Consejo Nacional de Investigaciones Científicas y Técnicas (Conicet), Ciudad Autónoma de Buenos Aires, Argentina.
authors.forename: María E
authors.initials: ME
authors.lastname: Primo
authors.forename: Jean
authors.initials: J
authors.lastname: Jakoncic
authors.forename: Martín E
authors.initials: ME
authors.lastname: Noguera
authors.forename: Valeria A
authors.initials: VA
authors.lastname: Risso
authors.forename: Laura
authors.initials: L
authors.lastname: Sosa
authors.forename: Mauricio P
authors.initials: MP
authors.lastname: Sica
authors.forename: Michele
authors.initials: M
authors.lastname: Solimena
authors.forename: Edgardo
authors.initials: E
authors.lastname: Poskus
authors.forename: Mario R
authors.initials: MR
authors.lastname: Ermácora
mesh_terms: D001665:Binding Sites; D002118:Calcium / Q000737:chemistry; D002467:Cell Nucleus / Q000378:metabolism; D003460:Crystallization; D018360:Crystallography, X-Ray / Q000379:methods; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007328:Insulin / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D025941:Protein Interaction Mapping; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry; D013499:Surface Properties
chemical_list: D007328:Insulin; D012997:Solvents; D004247:DNA; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D002118:Calcium