Gene[MULE](/entities/mule)
UniProt[Q9Y4D8](https://www.uniprot.org/uniprot/Q9Y4D8)
PDB Structures4LJU, 5MVO
Molecular Weight523,000 Da
Subcellular LocalizationNucleus, Cytoplasm
Protein FamilyHECT-type E3 ubiquitin ligase, MULE/ARF-BP1 family
MULE (MCL1-ubiquitin ligase E3), also known as ARF-BP1 (ARF-binding protein 1), is a HECT-type E3 ubiquitin ligase with diverse cellular functions. MULE targets multiple substrates including the anti-apoptotic protein MCL1, p53, and chromatin regulators. In the nervous system, MULE plays roles in neuronal survival, DNA damage response, and protein homeostasis relevant to neurodegenerative diseases.
MULE contains multiple functional domains:
- HECT Domain (3080-3458): Catalytic domain for ubiquitin transfer
- MUE domain: Substrate recognition
- CHDomain: DNA binding
- WD40 repeats: Protein-protein interactions
The HECT domain at the C-terminus mediates ubiquitin conjugation, while N-terminal regions confer substrate specificity.
In neurons, MULE regulates:
- Apoptosis: Targets MCL1 for degradation, linking DNA damage to cell death
- p53 regulation: Controls p53 stability and transcriptional activity
- DNA damage response: Ubiquitinates checkpoint proteins
- Chromatin remodeling: Regulates histone modification enzymes
- Protein quality control: Participates in ER-associated degradation
MULE expression is developmentally regulated in the brain with highest levels during synaptic plasticity periods.
- Neuronal apoptosis: MULE-mediated MCL1 degradation promotes neuronal death in AD
- DNA damage: MULE dysregulation impairs neuronal DNA repair
- p53 pathway: Altered p53 regulation contributes to Aβ-induced toxicity
- Mitochondrial apoptosis: MULE regulates dopaminergic neuron survival through MCL1
- Oxidative stress: MULE responds to oxidative DNA damage
- Protein clearance: MULE may affect α-synuclein degradation pathways
- Motor neuron survival: MULE influences motor neuron viability
- Protein aggregation: MULE dysfunction may contribute to ubiquitin system impairment
- DNA repair deficits: MULE regulates DNA repair capacity in neurons
¶ Stroke and Brain Ischemia
- Ischemic injury: MULE mediates neuronal death after cerebral ischemia
- Therapeutic target: MULE inhibition may protect against stroke damage
- MULE inhibitors could protect neurons from apoptosis
- MCL1 stabilizers indirectly reduce MULE pro-apoptotic effects
- Conditional knockout mice for neuronal studies
- siRNA/shRNA for knockdown experiments
- In vitro ubiquitination assays with recombinant protein
- Zhong et al., MULE in neuronal apoptosis (2022)
- Chen et al., MULE and p53 in neurodegeneration (2021)
- Liu et al., MULE as therapeutic target in PD (2023)