PMID:24905733

Citation	Flach, K, Ramminger, E, Hilbrich, I, Arsalan-Werner, A, Albrecht, F, Herrmann, L, Goedert, M, Arendt, T and Holzer, M (2014) Axotrophin/MARCH7 acts as an E3 ubiquitin ligase and ubiquitinates tau protein in vitro impairing microtubule binding. Biochim. Biophys. Acta 1842:1527-38
Abstract	Tau is the major microtubule-associated protein in neurons involved in microtubule stabilization in the axonal compartment. Changes in tau gene expression, alternative splicing and posttranslational modification regulate tau function and in tauopathies can result in tau mislocalization and dysfunction, causing tau aggregation and cell death. To uncover proteins involved in the development of tauopathies, a yeast two-hybrid system was used to screen for tau-interacting proteins. We show that axotrophin/MARCH7, a RING-variant domain containing protein with similarity to E3 ubiquitin ligases interacts with tau. We defined the tau binding domain to amino acids 552-682 of axotrophin comprising the RING-variant domain. Co-immunoprecipitation and co-localization confirmed the specificity of the interaction. Intracellular localization of axotrophin is determined by an N-terminal nuclear targeting signal and a C-terminal nuclear export signal. In AD brain nuclear localization is lost and axotrophin is rather associated with neurofibrillary tangles. We find here that tau becomes mono-ubiquitinated by recombinant tau-interacting RING-variant domain, which diminishes its microtubule-binding. In vitro ubiquitination of four-repeat tau results in incorporation of up to four ubiquitin molecules compared to two molecules in three-repeat tau. In summary, we present a novel tau modification occurring preferentially on 4-repeat tau protein which modifies microtubule-binding and may impact on the pathogenesis of tauopathies.
Links	PubMed PMC4311138 Online version:10.1016/j.bbadis.2014.05.029
Keywords	Aged; Alzheimer Disease/metabolism; Alzheimer Disease/pathology; Animals; Blotting, Western; Brain/metabolism; Case-Control Studies; Cell Proliferation; Cells, Cultured; Humans; Immunoenzyme Techniques; Immunoprecipitation; Mice; Mice, Knockout; Microtubules/metabolism; Protein Binding; Recombinant Proteins/metabolism; Two-Hybrid System Techniques; Ubiquitin/metabolism; Ubiquitin-Protein Ligases/metabolism; Ubiquitination; tau Proteins/physiology
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:MARH7		GO:0006513: protein monoubiquitination	ECO:0000314:		P		The organism is H. Sapiens and the Protein is March7 but it referred as axotrophin in the journal. Figure 3E shows that MARCH7 (E3 ubiquitin-protein ligase MARCH7) ubiquitinates tau (Microtubule-associated protein tau)	complete CACAO 13038

References

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