E3 ubiquitin-protein ligase MARCH5, also known as membrane-associated ring finger (C3HC4) 5, is an

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

that, in humans, is encoded by the ''MARCH5''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

. It is localized in the

mitochondrial A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...

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 A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) which stabilizes the fold. The term ''zinc finger'' was originally coined to describe the finger-like appearance of a hy ...

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 Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...

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 The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...

. 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 Fission, a splitting of something into two or more parts, may refer to: * Fission (biology), the division of a single entity into two or more parts and the regeneration of those parts into separate entities resembling the original * Nuclear fissio ...

, 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 Microtubule-associated protein 1B is a protein that in humans is encoded by the ''MAP1B'' gene. Function This gene encodes a protein that belongs to the microtubule-associated protein family. The proteins of this family are thought to be invol ...

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 receptor Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-pass membrane protein, single-spanning receptor (biochemistry), receptors usually expressed on sentinel cells such as macrophages ...

s (TLRs), which recognize distinct

pathogen In biology, a pathogen (, "suffering", "passion" and , "producer of"), in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a Germ theory of d ...

-associated molecular patterns and play a critical role in the

innate immune response The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates (the other being the adaptive immune system). The innate immune system is an alternate defense strategy and is the dominant immune s ...

. 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 Septins are a group of guanosine triphosphate, GTP-molecular binding, binding proteins gene expression, expressed in all eukaryote, eukaryotic cells except plants. Different septins form protein complexes with each other. These complexes can fur ...

genes, care must be exercised when analyzing genetic data containing the MARCH5 gene in

Microsoft Excel Microsoft Excel is a spreadsheet editor developed by Microsoft for Microsoft Windows, Windows, macOS, Android (operating system), Android, iOS and iPadOS. It features calculation or computation capabilities, graphing tools, pivot tables, and a ...

. 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.