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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.

SUBMITTER: Nadella M

PROVIDER: S-EPMC1277968 | biostudies-literature | 2005 Nov

REPOSITORIES: biostudies-literature

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Structure and activity of the axon guidance protein MICAL.

Nadella Mythili M Bianchet Mario A MA Gabelli Sandra B SB Barrila Jennifer J Amzel L Mario LM

Proceedings of the National Academy of Sciences of the United States of America 20051107 46

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, ...[more]

PMID: 16275926

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Project description:During the development of the Drosophila central nervous system the process of midline crossing is orchestrated by a number of guidance receptors and ligands. Many key axon guidance molecules have been identified in both invertebrates and vertebrates, but the transcriptional regulation of growth cone guidance remains largely unknown. One open question is whether transcriptional regulation plays a role in midline crossing, or if local translation can account for the necessary fine tuning of protein levels. To investigate this issue, we conducted a genome wide analysis of transcription in Drosophila embryos using wild type and a number of well-characterized Drosophila guidance mutants and transgenics. We also analyzed a publicly available microarray time course of Drosophila embryonic development with an axon guidance focus. Using hopach, a novel clustering method which is well suited to microarray data analysis, we identified groups of genes with similar expression patterns across guidance mutants and transgenics. We then systematically characterized the resulting clusters with respect to their relevance to axon guidance using two complementary controlled vocabularies: the Gene Ontology (GO) and anatomical annotations of the Atlas of Pattern of Gene Expression (APoGE) in situ hybridization database. The analysis indicates that regulation of gene expression does play a role in the process of axon guidance in Drosophila. We also find a strong link between axon guidance and hemocyte migration, a result that agrees with mounting evidence that axon guidance molecules are co-opted in vertebrate vascularization. Cell cyclin activity in the context of axon guidance is also suggested from our array data. RNA and protein patterns of cell cyclin in axon guidance mutants and transgenics support this possible link. This study provides important insights into the regulation of axon guidance in vivo and suggests that transcription does play a role in control of axon guidance. Keywords: Mutant Analysis

Dataset Information

Structure and activity of the axon guidance protein MICAL.

Publications

Structure and activity of the axon guidance protein MICAL.

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