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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Sequence
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Axons*
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Cloning, Molecular
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Crystallography, X-Ray
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Flavin-Adenine Dinucleotide / metabolism
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Hydrogen Peroxide / metabolism
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Kinetics
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Microfilament Proteins
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Microtubule-Associated Proteins / chemistry*
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism
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Microtubule-Associated Proteins / physiology*
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Mixed Function Oxygenases / chemistry*
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Mixed Function Oxygenases / genetics
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Mixed Function Oxygenases / metabolism
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Mixed Function Oxygenases / physiology*
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Models, Molecular
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Molecular Sequence Data
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NADP / metabolism
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Protein Conformation
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Sequence Homology, Amino Acid
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Structure-Activity Relationship
Substances
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Microfilament Proteins
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Microtubule-Associated Proteins
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Flavin-Adenine Dinucleotide
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NADP
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Hydrogen Peroxide
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Mical1 protein, mouse
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Mixed Function Oxygenases