dynamin-1-like protein; Dnm1p/Vps1p-like protein; DVLP; dynamin family member proline-rich carboxyl-terminal domain less; Dymple; dynamin-like protein; dynamin-like protein 4; dynamin-like protein IV; HdynIV; dynamin-related protein 1 (DNM1L, DLP1, DRP1)
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Function
- functions in mitochondrial & peroxisomal division
- mediates membrane fission through oligomerization into ring-like structures which wrap around the scission site to constict & sever the mitochondrial membrane through a GTP hydrolysis-dependent mechanism
- required for normal brain development
- facilitates developmentally-regulated apoptosis during neural tube development
- required for a normal rate of cytochrome c release & caspase activation during apoptosis
- also required for mitochondrial fission during mitosis
- may be involved in vesicle transport
- isoform 1 & isoform 4 inhibit peroxisomal division when overexpressed
- phosphorylation/dephosphorylation events on two sites near the GED domain regulate mitochondrial fission
- phosphorylation on Ser-637 inhibits mitochondrial fission probably through preventing intramolecular interaction
- dephosphorylated on Ser-637 by PPP3CA which promotes mitochondrial fission
- phosphorylation on Ser-616 also promotes mitochondrial fission
- sumoylated on various lysine residues within the B domain, probably by MUL1
- sumoylation positively regulates mitochondrial fission
- desumoylated by SENP5 during G2/M transition of mitosis appears to be linked to its catalytic activity
- S-nitrosylation increases DNM1L dimerization, mitochondrial fission & causes neuronal damage
- ubiquitination by MARCH5 affects mitochondrial morphology
- homotetramer; dimerizes through the N-terminal GTP-middle region of one molecule binding to the GED domain of another DNM1L molecule
- can self-assemble in multimeric ring-like structures
- interacts with BCL2L1
- interaction stimulates GTPase activity of DMN1L in synapses & increases the number of axonal mitochondria & the size & number of synaptic vesicle clusters
- interacts with FIS1 (putative)
- interacts with GSK3B & MARCH5
- interacts (via the GTPase & B domains) with UBE2I
- interaction promotes sumoylation of DNM1L, mainly in ite B domain
- interacts with PPP3CA
- interaction dephosphorylates DNM1L & regulates its transition to mitochondria
- interacts with MID49 & MID51
Structure
- the GED domain folds back to interact, in cis, with the GTP-binding domain & middle domain, & interacts, in trans, with the GED domains of other DNM1L molecules, & is thus critical for activating GTPase activity & for DNM1L dimerization
- belongs to the dynamin family
- contains 1 GED domain
Compartment
- cytoplasm, Golgi, endomembrane system
- mainly cytosolic
- translocated to the mitochondrial membrane through interaction with FIS1
- colocalized with MARCH5 at mitochondrial membrane
- localizes to mitochondria at sites of division
- associated with peroxisomal membranes, partly recruited there by PEX11B
- may also be associated with endoplasmic reticulum tubules & cytoplasmic vesicles & found to be perinuclear
- in some cell types, localizes to the Golgi complex
Alternative splicing
named isoforms=6
Expression
- ubiquitously expressed
- highest levels found in skeletal muscles, heart, kidney & brain
- isoform 1 is brain-specific
- isoform 2 is predominantly expressed in testis
- isoform 3 is predominantly expressed in skeletal muscle
- isoform 4 is weakly expressed in brain, heart & kidney
- isoform 5 is predominantly expressed in liver, heart & kidney
- isoform 6 is expressed in neurons
Pathology
- may be associated with Alzheimer disease through
- beta-amyloid-induced increased S-nitrosylation of DNM1L, which triggers, directly or indirectly, excessive mitochondrial fission, synaptic loss & neuronal damage
- defects in DNM1L are the cause EMPF encephalopathy
Comparative biology
- hyperactivation in oligodendrocytes may inhibit hexokinase-1 inhibiting glycolysis & triggering NLRP3 inflammasome activation resulting in white matter degeneration in a mouse model for Alzheimer's disease[2]
More general terms
Additional terms
References
- ↑ UniProt http://www.uniprot.org/uniprot/O00429.html
- ↑ 2.0 2.1 Zhang X, Wang R, Hu D et al Oligodendroglial glycolytic stress triggers inflammasome activation and neuropathology in Alzheimer's disease. Science Advances 2020. Vol. 6, no. 49, eabb8680. Dec 4 PMID: https://www.ncbi.nlm.nih.gov/pubmed/33277246 PMCID: PMC7717916 Free PMC article https://advances.sciencemag.org/content/6/49/eabb8680