Alternative titles; symbols
HGNC Approved Gene Symbol: MICAL1
Cytogenetic location: 6q21 Genomic coordinates (GRCh38) : 6:109,444,062-109,465,968 (from NCBI)
MICAL1 is involved in regulation of actin microfilaments (Giridharan et al., 2012).
Using Far Western screening of a thymus cDNA library, Suzuki et al. (2002) isolated a cDNA encoding MICAL, which interacts with the SH3 domain of CASL (HEF1; 602265). The 118-kD, 1,067-amino acid MICAL protein has a calponin homology domain, a LIM domain, a putative leucine zipper motif, and a proline-rich PPKPP sequence. MICAL associates with CASL through the PPKPP sequence. Northern blot analysis of hematopoietic cell lines and murine tissues showed that MICAL is expressed in thymus, lung, spleen, kidney, testis, and hematopoietic cells. MICAL is a cytoplasmic protein that colocalizes with CASL at the perinuclear area. Through its C-terminal region, MICAL also associates with vimentin (193060), a major component of intermediate filaments. Immunostaining revealed that MICAL localizes along with vimentin intermediate filaments. These results suggested that MICAL may be a cytoskeletal regulator that connects CASL to intermediate filaments.
By protein sequence analysis, Weide et al. (2003) showed that human MICAL1 protein contains a flavoprotein monooxygenase domain, a calponin homology (CH) domain, and a LIM domain. Additionally, they identified 2 putative coiled-coil (cc) domains in the C-terminal region, a putative rab1 binding site, and a highly charged polyglutamic acid stretch. MICAL1 contains 2 splice variants, referred to as MICAL1a and MICAL1b, encoding 2 isoforms of 1067 and 981 amino acids, respectively. Cell fractionation analysis revealed that MICAL1 was predominantly localized to cytosol.
Using immunofluorescence assays, Giridharan et al. (2012) confirmed that HA-tagged MICAL1 localized to the cytoplasm of transfected HeLa cells.
Weide et al. (2003) determined that the human MICAL1 gene consists of 25 exons.
By radiation hybrid analysis, Suzuki et al. (2002) mapped the MICAL gene to chromosome 6q16.16.
Stumpf (2024) mapped the MICAL1 gene to chromosome 6q21 based on an alignment of the MICAL1 sequence (GenBank BC042144) with the genomic sequence (GRCh38).
Terman et al. (2002) showed that Drosophila Mical, a large, multidomain, cytosolic protein expressed in axons, interacts with the neuronal plexin A (Plexa; see 601055) receptor and is required for semaphorin-1A (Sema1a)-Plexa-mediated repulsive axon guidance. In addition to containing several domains known to interact with cytoskeletal components, Mical has a flavoprotein monooxygenase domain, the integrity of which is required for Sema1a-Plexa repulsive axon guidance. Vertebrate orthologs of Drosophila Mical are neuronally expressed and also interact with vertebrate plexins, and monooxygenase inhibitors abrogate semaphorin-mediated axonal repulsion. These results suggested a novel role for oxidoreductases in repulsive neuronal guidance.
By a yeast 2-hybrid screen of a human placenta cDNA library, Weide et al. (2003) identified human MICAL1 as an interacting protein of the Rab1 GTPase RAB1B (612565). The interaction was confirmed by pull-down experiments, and only active RAB1B showed a strong interaction, indicating that the interaction was nucleotide-dependent. Deletion mutation analysis revealed that the RAB1 interacting domain was in the C-terminal portion of the MICAL1 protein. Cell fractionation analysis indicated that the interaction between MICAL1 and RAB1B was also present in human cells.
Hung et al. (2010) reported that Drosophila Mical directly links semaphorins and their plexin receptors to the precise control of actin filament (F-actin) dynamics. The authors found that Mical is both necessary and sufficient for semaphorin-plexin-mediated F-actin reorganization in vivo. Likewise, purified Mical protein directly bound F-actin and disassembled both individual and bundled actin filaments. Mical utilized its redox activity to alter F-actin dynamics in vivo and in vitro, indicating a previously unknown role for specific redox signaling events in actin cytoskeletal regulation. Hung et al. (2010) concluded that Mical therefore is a novel F-actin disassembly factor that provides a molecular conduit through which actin reorganization, a hallmark of cell morphologic changes including axon navigation, can be precisely achieved spatiotemporally in response to semaphorins.
Hung et al. (2011) described a biochemical process that was able to disassemble actin filaments and limit their reassembly. Actin was a specific substrate of the multidomain oxidation-reduction enzyme, Mical, an actin disassembly factor that directly responds to semaphorin (see 601124)/plexin (e.g., 601054) extracellular repulsive cues. Actin filament subunits were directly modified by Mical on their conserved pointed-end, which is critical for filament assembly. Mical posttranslationally oxidized the methionine-44 residue within the D-loop of actin, simultaneously severing filaments and decreasing polymerization. Hung et al. (2011) concluded that this mechanism underlying actin cytoskeletal collapse may have broad physiologic and pathologic ramifications.
Giridharan et al. (2012) found that MICAL2 (608881) overexpression in HeLa cells induced loss of actin stress fibers and generation of actin-rich protrusions. The MICAL2 FAD domain was both required and sufficient for actin stress fiber loss. MICAL1 overexpression did not induce loss of actin stress fibers. However, overexpression of MICAL1 lacking its C-terminal coiled-coil domain led to a dramatic reduction in actin stress fibers, as well as decreased levels of overall F-actin. The findings suggested that the FAD domains of MICAL1 and MICAL2 are both actin stress fiber regulators, but that the coiled-coil domain, which is present in MICAL1 but absent in MICAL2, is self-inhibitory. In line with these results, depletion of either MICAL1 or MICAL2 induced generation of actin-rich protrusions, and generation of actin-rich protrusions induced by MICAL1 depletion could be partially rescued by reintroduction of MICAL1. Further analysis revealed that MICAL proteins exerted their effects on actin microfilaments, at least in part, through generation of reactive oxygen species (ROS) via their FAD domains. However, self-inhibitory MICAL1 was unable to generate ROS unless its coiled-coil domain was removed.
By mass spectrometry analysis, Konstantinidis et al. (2020) identified methionine-308 (M308), a highly conserved residue in the calmodulin (CaM)-binding domain of CaMKII (114078), as a target for MICAL1-catalyzed oxidation and MSRB (606216)-catalyzed reduction, which was supported by subsequent structural analysis. MICAL1 oxidized M308 of CaMKII to M308-sulfoxide (M308-SO), and this reaction could be reversed by MSRB (606216). CaMKII activation was not required for M308 oxidation by MICAL1, and redox modulation of M308 regulated CaMKII activity by controlling its CaM binding, as M308-SO significantly decreased CaMKII binding to Ca(2+)/CaM,
Konstantinidis et al. (2020) found that CaMkII was excessively activated in the hearts of Mical1 -/- mice, and that hyperactivation of CaMkII contributed to excess mortality after pathologic myocardial stress. For further analysis, the authors identified a Mical1 R116H mutant that could distinguish F-actin and CaMkII, as the mutant selectively lost the actin targeting function but retained the protection against CaMkII hyperactivation. Accordingly, Mical1 R116H knockin mice were born at mendelian ratios with no obvious morphometric differences compared with wildtype, and they were protected from the excessive mortality seen with Mical1 -/- mice. These results suggested that Mical1 constrained CaMkII activity in vivo, that loss of Mical1 activity was sufficient to promote CaMkII-triggered heart disease, and that these observations were not due to loss of Mical1 functions related to actin oxidation. In vitro analysis demonstrated that M308 was a redox switch that determined CaMkII activity, as M308-SO and M308V, a hypomorphic but not inactive mutant mimicking M308-SO, profoundly reduced Ca(2+)/CaM binding and subsequent CaMKII activity. This M308 regulation of CaMkII responses by controlling Ca(2+)/CaM binding was further confirmed in vivo in CaMKII-delta M308V mice and in Drosophila. Mathematical modeling predicted that modification of CaMKII M308 by oxidation or mutation to M308V could significantly inhibit CaMKII activity in catecholaminergic polymorphic ventricular tachycardia (CPVT). In agreement, introduction of M308V mutation in cardiomyocytes with CPVT derived from human induced pluripotent stem cells (hiPSCs) prevented CaMKII hyperactivation.
Giridharan, S. S., Rohn, J. L., Naslavsky, N., Caplan, S. Differential regulation of actin microfilaments by human MICAL proteins. J. Cell Sci. 125: 614-624, 2012. [PubMed: 22331357] [Full Text: https://doi.org/10.1242/jcs.089367]
Hung, R.-J., Pak, C. W., Terman, J. R. Direct redox regulation of F-actin assembly and disassembly by Mical. Science 334: 1710-1713, 2011. [PubMed: 22116028] [Full Text: https://doi.org/10.1126/science.1211956]
Hung, R.-J., Yazdani, U., Yoon, J., Wu, H., Yang, T., Gupta, N., Huang, Z., van Berkel, W. J. H., Terman, J. R. Mical links semaphorins to F-actin disassembly. Nature 463: 823-827, 2010. [PubMed: 20148037] [Full Text: https://doi.org/10.1038/nature08724]
Konstantinidis, K., Bezzerides, V. J., Lai, L., Isbell, H. M., Wei, A.-C., Wu, Y., Viswanathan, M. C., Blum, I. D., Granger, J. M., Heims-Waldron, D., Zhang, D., Luczak, E. D., and 16 others. MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII. J. Clin. Invest. 130: 4663-4678, 2020. [PubMed: 32749237] [Full Text: https://doi.org/10.1172/JCI133181]
Stumpf, A. M. Personal Communication. Baltimore, Md. 07/25/2024.
Suzuki, T., Nakamoto, T., Ogawa, S., Seo, S., Matsumura, T., Tachibana, K., Morimoto, C., Hirai, H. MICAL, a novel CasL interacting molecule, associates with vimentin. J. Biol. Chem. 277: 14933-14941, 2002. [PubMed: 11827972] [Full Text: https://doi.org/10.1074/jbc.M111842200]
Terman, J. R., Mao, T., Pasterkamp, R. J., Yu, H.-H., Kolodkin, A. L. MICALs, a family of conserved flavoprotein oxidoreductases, function in plexin-mediated axonal repulsion. Cell 109: 887-900, 2002. [PubMed: 12110185] [Full Text: https://doi.org/10.1016/s0092-8674(02)00794-8]
Weide, T., Teuber, J., Bayer, M., Barnekow, A. MICAL-1 isoforms, novel rab1 interacting proteins. Biochem. Biophys. Res. Commun. 306: 79-86, 2003. [PubMed: 12788069] [Full Text: https://doi.org/10.1016/s0006-291x(03)00918-5]