title: Structure and activity of the axon guidance protein MICAL.
abstract: During development, neurons are guided to their targets by short- and long-range attractive and repulsive cues. MICAL, a large multidomain protein, is required for the combined action of semaphorins and plexins in axon guidance. Here, we present the structure of the N-terminal region of MICAL (MICAL(fd)) determined by x-ray diffraction to 2.0 A resolution. The structure shows that MICAL(fd) is an FAD-containing module structurally similar to aromatic hydroxylases and amine oxidases. In addition, we present biochemical data that show that MICAL(fd) is a flavoenzyme that in the presence of NADPH reduces molecular oxygen to H(2)O(2) (K(m,NAPDH) = 222 microM; k(cat) = 77 sec(-1)), a molecule with known signaling properties. We propose that the H(2)O(2) produced by this reaction may be one of the signaling molecules involved in axon guidance by MICAL.
authors.affiliation: Department of Biophysics and Biophysical Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Mythili
authors.initials: M
authors.lastname: Nadella
authors.forename: Mario A
authors.initials: MA
authors.lastname: Bianchet
authors.forename: Sandra B
authors.initials: SB
authors.lastname: Gabelli
authors.forename: Jennifer
authors.initials: J
authors.lastname: Barrila
authors.forename: L Mario
authors.initials: LM
authors.lastname: Amzel
mesh_terms: D000595:Amino Acid Sequence; D001369:Axons; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D007700:Kinetics; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006899:Mixed Function Oxygenases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009249:NADP / Q000378:metabolism; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D005182:Flavin-Adenine Dinucleotide; D009249:NADP; D006861:Hydrogen Peroxide; C507541:Mical1 protein, mouse; D006899:Mixed Function Oxygenases