Biology:MARCH5

Generic protein structure example

E3 ubiquitin-protein ligase MARCH5, also known as membrane-associated ring finger (C3HC4) 5, is an enzyme that, in humans, is encoded by the MARCH5 gene. It is localized in the mitochondrial outer membrane and has four transmembrane domains.

Structure

Gene

The human gene MARCH5, also known as MITOL or RNF153, has 7 Exons and locates at the chromosome band 10q23.32-q23.33.

Protein

The human E3 ubiquitin-protein ligase MARCH5 protein, a member of the transmembrane RING‐finger protein family is 31 kDa in size and composed of 278 amino acids with a N-terminal Zinc-finger domain at amino acid sequence 6-75 and four C-terminal transmembrane spans. The theoretical PI of this protein is 9.00.

Function

As an E3 ubiquitin ligases, enzyme MARCH 5 catalyzes the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to an identified protein substrate. MARCH5 was firstly identified as a mitofusin 2- and Drp1-binding protein. MARCH5 promotes ubiquitination of Drp1 and a knockdown of MARCH5 is by RNAi led to abnormal mitochondrial fusion. Further evidences show that MARCH 5 specifically interacts with mitofusin 1, by reducing the levels of it during certain phases of the cell cycle. Given the facts that MARCH5 regulates the protein proteostasis of Drp1, mitofusin 1, and mitofusin 2 that are pivotal regulators of mitochondrial fusion and fission, MARCH5 is critical for the regulation of standard mitochondria morphology, and deficiencies in it promote cellular senescence.

Clinical significance

Considering that both Drp1 and MAP1B are substrates for MITOL, MITOL is thought to play a protective role against nitrosative stress-mediated disruption of mitochondrial dynamics such as morphological stability and transport of mitochondria. As significantly decreased expression of MITOL occurs in response to ageing in normal tissues, MITOL may control ageing by regulating the production of ROS in mitochondria. From a pathological perspective, in a neuronal cell model, dominant-negative MARCH5 prevents mitochondrial fragmentation during neurodegenerative stress induced by the neuron-specific reactive oxygen generator 6-hydroxydopamine, the complex I inhibitor rotenone or Alzheimer's-related amyloid beta peptide. MARCH5 is also involved in the removal of proteins associated with specific neurodegenerative disorders such as ataxin-3 in Machado–Joseph disease or mSOD1 in amyotrophic lateral sclerosis likely supporting mitochondrial function. MARCH5 has also been linked to toll-like receptors (TLRs), which recognize distinct pathogen-associated molecular patterns and play a critical role in the innate immune response.

Ubiquitin-dependent degradation pathways have clear cancer relevance due to their integral involvement in protein quality control, regulation of immune responses, signal transduction, and cell cycle regulation.

Gene name error in Excel

Like the other MARCH and septin genes, care must be exercised when analyzing genetic data containing the MARCH5 gene in Microsoft Excel. This is due to Excel's autocorrect feature treating the MARCH gene as a date and converting it to a standard date format. The original text cannot be recovered as a result of the conversion. A 2016 study found up to 19.6% of all papers in selected journals to be affected by the gene name error. The issue can be prevented by using an alias name such as MARCHF5, prepending with an apostrophe ('), or preformatting the cell as text.

Further reading

• "The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division". The Journal of Cell Biology 178 (1): 71–84. Jul 2007. doi:10.1083/jcb.200611064. PMID 17606867. 
• "MARCH-V is a novel mitofusin 2- and Drp1-binding protein able to change mitochondrial morphology". EMBO Reports 7 (10): 1019–22. Oct 2006. doi:10.1038/sj.embor.7400790. PMID 16936636. 
• "A novel mitochondrial ubiquitin ligase plays a critical role in mitochondrial dynamics". The EMBO Journal 25 (15): 3618–26. Aug 2006. doi:10.1038/sj.emboj.7601249. PMID 16874301. 
• "Inhibition of MARCH5 ubiquitin ligase abrogates MCL1-dependent resistance to BH3 mimetics via NOXA". Oncotarget 7 (13): 15986–6002. Feb 2016. doi:10.18632/oncotarget.7558. PMID 26910119.