title: Myelin 2',3'-cyclic nucleotide 3'-phosphodiesterase: active-site ligand binding and molecular conformation.
abstract: The 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) is a highly abundant membrane-associated enzyme in the myelin sheath of the vertebrate nervous system. CNPase is a member of the 2H phosphoesterase family and catalyzes the formation of 2'-nucleotide products from 2',3'-cyclic substrates; however, its physiological substrate and function remain unknown. It is likely that CNPase participates in RNA metabolism in the myelinating cell. We solved crystal structures of the phosphodiesterase domain of mouse CNPase, showing the binding mode of nucleotide ligands in the active site. The binding mode of the product 2'-AMP provides a detailed view of the reaction mechanism. Comparisons of CNPase crystal structures highlight flexible loops, which could play roles in substrate recognition; large differences in the active-site vicinity are observed when comparing more distant members of the 2H family. We also studied the full-length CNPase, showing its N-terminal domain is involved in RNA binding and dimerization. Our results provide a detailed picture of the CNPase active site during its catalytic cycle, and suggest a specific function for the previously uncharacterized N-terminal domain.
authors.affiliation: Department of Biochemistry and Biocenter Oulu, University of Oulu, Oulu, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Myllykoski
authors.forename: Arne
authors.initials: A
authors.lastname: Raasakka
authors.forename: Huijong
authors.initials: H
authors.lastname: Han
authors.forename: Petri
authors.initials: P
authors.lastname: Kursula
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D002384:Catalysis; D020134:Catalytic Domain; D019343:Citric Acid / Q000737:chemistry; D018360:Crystallography, X-Ray / Q000379:methods; D019281:Dimerization; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009186:Myelin Sheath / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012313:RNA / Q000737:chemistry; D013431:Sulfates / Q000737:chemistry
chemical_list: D008024:Ligands; D013431:Sulfates; D019343:Citric Acid; D012313:RNA; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases