DNM2 Protein

DNM2 Protein (Dynamin 2)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">DNM2 Protein</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>DNM2</td>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Dynamin-2</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>DNM2, Dynamin II</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P50570</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~98 kDa</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Dynamin family (large GTPases)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Ubiquitous; highest in brain (neurons), testis, skeletal muscle</td>
</tr>
<tr>
<td class="label">Cellular Location</td>
<td>Cytoplasm, plasma membrane, Golgi apparatus, mitochondria</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Introduction

Dnm2 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

...

DNM2 Protein (Dynamin 2)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">DNM2 Protein</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>DNM2</td>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>Dynamin-2</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>DNM2, Dynamin II</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P50570</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~98 kDa</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Dynamin family (large GTPases)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Ubiquitous; highest in brain (neurons), testis, skeletal muscle</td>
</tr>
<tr>
<td class="label">Cellular Location</td>
<td>Cytoplasm, plasma membrane, Golgi apparatus, mitochondria</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

Introduction

Dnm2 Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

DNM2 (Dynamin 2) is a large GTPase belonging to the dynamin family of membrane remodeling proteins. It plays essential roles in membrane fission reactions during various cellular trafficking pathways, including clathrin-mediated endocytosis, synaptic vesicle recycling, mitochondrial dynamics, and receptor internalization. As a ubiquitously expressed protein with particularly high levels in the brain and testis, DNM2 is critical for neuronal function and synaptic transmission. Mutations in DNM2 cause several inherited human diseases, including Charcot-Marie-Tooth disease (CMT) and centronuclear myopathy (CNM), highlighting its importance in both nervous system and muscle physiology. [@itoh2005]

Protein Information

Molecular Function

GTPase Activity and Mechanism

DNM2 functions as a molecular machine that couples GTP hydrolysis to mechanical work: [@wang2006]

GTP Binding: DNM2 assembles into rings around necked membrane vesicles in its GTP-bound active state [1]

Membrane Recognition: The PH domain binds to phosphoinositides (PIP2) on target membranes, targeting DNM2 to clathrin-coated pits and other budding vesicles [2]

Conformational Change: GTP hydrolysis triggers a dramatic conformational constriction that physically severing the connecting membrane neck [3]

GTP Hydrolysis: The GAP (GTPase activating protein) domain accelerates GTP hydrolysis, providing the energy for membrane fission [4]

Disassembly: Following fission, DNM2 disassembles for recycling [5]

Role in Endocytosis

• Clathrin-Mediated Endocytosis (CME): DNM2 is the canonical membrane fission enzyme for clathrin-coated vesicle formation [6]
• Synaptic Vesicle Recycling: Essential for recycling synaptic vesicles after neurotransmitter release [7]
• Receptor Internalization: Regulates surface receptor density through controlled internalization [8]
• Cargo Selection: Interfaces with adaptors to ensure specific cargo inclusion [9]

Mitochondrial Dynamics

• Mitochondrial Fission: DNM2 works with [DRP1](/proteins/drp1-protein) (DNM1L) to mediate mitochondrial division [10]
• Mitochondrial Quality Control: Enables mitophagy by generating fission products for selective degradation [11]
• [Apoptosis](/entities/apoptosis) Regulation: Pro-apoptotic stimuli trigger DNM2 recruitment to mitochondria [12]

Structure-Function Relationships

Domain Architecture

DNM2 contains multiple functional domains that enable its membrane remodeling activity: [@warnock1997]

N-terminal GTPase Domain (Residues 1-300): Catalyzes GTP hydrolysis; mutations in this domain impair fission activity [13]

Middle Domain (Residues 300-500): Mediates DNM2 self-assembly into oligomers/rings [14]

Pleckstrin Homology (PH) Domain (Residues 500-600): Binds phosphoinositides; targets DNM2 to membrane surfaces [15]

GTPase Effector Domain (GED, Residues 600-750): Regulates GTPase activity and coordinates oligomerization [16]

C-terminal Proline-Rich Domain (PRD, Residues 750-864): Binds SH3 domain proteins; enables regulatory interactions [17]

Oligomerization

DNM2 forms helical oligomers: [@klein1998]

• 10-14 protomers per ring
• Rings stack to form spirals
• ~40-80 DNM2 molecules per endocytic vesicle
• Oligomerization is required for fission activity

Disease Associations

Charcot-Marie-Tooth Disease (CMT)

• CMT Intermediate Type A: Dominant DNM2 mutations cause CMTDIA, characterized by progressive distal muscle weakness, atrophy, and sensory loss [18]
• Pathogenic Mechanisms:
• Gain-of-function mutations increase DNM2 activity, disrupting peripheral nerve myelination [19]
• Altered endocytic trafficking in Schwann cells impairs myelin maintenance [20]
• Dominant-negative effects disrupt normal DNM2 function [21]
• Clinical Features: Onset in adolescence or early adulthood, foot deformities, decreased reflexes, distal weakness
• Therapeutic Approaches: ASO-mediated allele silencing, gene therapy vectors [22]

Centronuclear Myopathy (CNM)

• Autosomal Dominant CNM: DNM2 mutations cause ~50% of inherited CNM cases [23]
• Pathology:
• Centralization of nuclei in muscle fibers
• Type I fiber atrophy
• Disorganized sarcolemmal architecture [24]
• Therapeutic Strategies: Antisense oligonucleotides targeting mutant alleles [25]

Amyotrophic Lateral Sclerosis (ALS)

• Synaptic Vesicle Dysfunction: DNM2-mediated endocytosis is impaired in ALS models [26]
• Neuromuscular Junction: DNM2 is critical for maintaining the presynaptic terminal [27]
• Therapeutic Target: Enhancing DNM2 function may protect vulnerable motor [neurons](/entities/neurons) [28]

Alzheimer's Disease

• APP Processing: DNM2 participates in [amyloid precursor protein](/entities/app-protein) internalization and processing [29]
• [Aβ](/proteins/amyloid-beta) Production: Altered endocytosis can affect Aβ generation and secretion [30]
• Synaptic Plasticity: DNM2 dysfunction may contribute to synaptic loss in AD [31]

Parkinson's Disease

• Synaptic Vesicle Recycling: DNM2-mediated endocytosis is essential for dopaminergic neuron function [32]
• LRRK2 Interaction: Pathogenic LRRK2 mutants may alter DNM2-dependent trafficking [33]
• Mitochondrial Quality Control: DNM2-mediated fission enables mitophagy in dopaminergic neurons [34]

Cancer

• Endocytosis in Tumor Biology: DNM2 regulates growth factor receptor internalization in cancer cells [35]
• Metastasis: DNM2 activity influences cell migration and invasion [36]

Therapeutic Implications

Small Molecule Inhibitors

• Dynamin Inhibitors: Dynasore, dyngo-4a block DNM2 GTPase activity [37]
• Specificity Limitations: First-generation inhibitors target all dynamins [38]

Gene Therapy Approaches

• ASO Therapy: Allele-specific antisense oligonucleotides for CMT [39]
• AAV Vectors: Gene replacement or silencing strategies [40]
• CRISPR Editing: Potential for precise mutant allele correction [41]

Modulator Development

• Phosphoinositide Modulators: Targeting membrane lipid composition [42]
• Kinase Inhibitors: Regulating DNM2 phosphorylation state [43]

Research Directions

Basic Science Priorities

Structural Biology: High-resolution structures of DNM2 on membranes

In Vivo Role: Tissue-specific knockout studies

Dynamin Isoforms: Understanding functional redundancy and specificity

Clinical Development

Biomarkers: DNM2 activity as disease progression marker

Patient Stratification: Genotype-phenotype correlations

Combination Therapies: Synergy with other therapeutic modalities

See Also

• [Charcot-Marie-Tooth Disease](/diseases/charcot-marie-tooth-disease)
• [Centronuclear Myopathy](/diseases/centronuclear-myopathy)
• [Amyotrophic Lateral Sclerosis](/diseases/als)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Synaptic Vesicle Recycling](/mechanisms/synaptic-vesicle-recycling)
• [Clathrin-Mediated Endocytosis](/mechanisms/clathrin-endocytosis)
• [Mitochondrial Dynamics](/mechanisms/mitochondrial-dynamics)
• [Dynamin 1](/proteins/dynamin-1)
• [Dynamin 3](/proteins/dynamin-3)
• [Synaptic Dysfunction Pathway](/mechanisms/synaptic-dysfunction-pathway)
• [Endocytosis Pathway](/mechanisms/endocytosis-pathway)

Background

The study of Dnm2 Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development. [@sever1999a]

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions. [@grabs1997]

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
• [Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
• [Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data

Additional evidence sources: [@zuchner2005] [@bolino2016] [@niemann2014] [@vittanen2017] [@burns2019] [@bitoun2005] [@jungbluth2017] [@cowling2017] [@saxena2005] [@shi2018] [@song2013] [@cao2020] [@zhou2011] [@gowrishankar2015] [@yin2019] [@dodson2012] [@yamada2014] [@menard2012] [@ball2016] [@macia2006] [@park2013] [@scholey2018] [@poirier2019] [@gyun2020] [@salazar2009] [@ahn2002]

References

[McNiven MA, et al, (2013) (2013)](https://pubmed.ncbi.nlm.nih.gov/14595332/)

[Itoh T, et al, (2005) (2005)](https://pubmed.ncbi.nlm.nih.gov/15821814/)

[Sweitzer SM, et al, (1998) (1998)](https://pubmed.ncbi.nlm.nih.gov/9671553/)

[Sever S, et al, (1999) (1999)](https://pubmed.ncbi.nlm.nih.gov/10531056/)

[Damke H, et al, (2001) (2001)](https://pubmed.ncbi.nlm.nih.gov/11586656/)

[Boucrot E, et al, (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/25855496/)

[Durieux AM, et al, (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20610765/)

[Sorkin A, et al, (2004) (2004)](https://pubmed.ncbi.nlm.nih.gov/15107853/)

[Schmid EM, et al, (2006) (2006)](https://pubmed.ncbi.nlm.nih.gov/16618850/)

[Lee JE, et al, (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/26965642/)

[Yamashita SI, et al, (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/27009394/)

[Karbowski M, et al, (2004) (2004)](https://pubmed.ncbi.nlm.nih.gov/15457261/)

[Wang L, et al, (2006) (2006)](https://pubmed.ncbi.nlm.nih.gov/16537651/)

[Warnock DE, et al, (1997) (1997)](https://pubmed.ncbi.nlm.nih.gov/9155022/)

[Klein DE, et al, (1998) (1998)](https://pubmed.ncbi.nlm.nih.gov/9813005/)

[Sever S, et al, (1999) (1999)](https://pubmed.ncbi.nlm.nih.gov/10467024/)

[Grabs D, et al, (1997) (1997)](https://pubmed.ncbi.nlm.nih.gov/9121475/)

[Zuchner S, et al, (2005) (2005)](https://pubmed.ncbi.nlm.nih.gov/15987438/)

[Bolino A, et al, (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/26993816/)

[Niemann A, et al, (2014) (2014)](https://pubmed.ncbi.nlm.nih.gov/25201963/)

[Vittanen M, et al, (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28385349/)

[Burns RJ, et al, (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31155743/)

[Bitoun M, et al, (2005) (2005)](https://pubmed.ncbi.nlm.nih.gov/15987439/)

[Jungbluth H, et al, (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28283423/)

[Cowling BS, et al, (2017) (2017)](https://pubmed.ncbi.nlm.nih.gov/28335014/)

[Saxena S, et al, (2005) (2005)](https://pubmed.ncbi.nlm.nih.gov/15960616/)

[Shi L, et al, (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/30059076/)

[Song Y, et al, (2013) (2013)](https://pubmed.ncbi.nlm.nih.gov/24367242/)

[Cao M, et al, (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32265644/)

[Zhou R, et al, (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21297262/)

[Gowrishankar S, et al, (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/25618954/)

[Yin G, et al, (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30617440/)

[Dodson MW, et al, (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22306812/)

[Yamada T, et al, (2014) (2014)](https://pubmed.ncbi.nlm.nih.gov/24753257/)

[Menard L, et al, (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/23136555/)

[Ball RY, et al, (2016) (2016)](https://pubmed.ncbi.nlm.nih.gov/27282250/)

[Macia E, et al, (2006) (2006)](https://pubmed.ncbi.nlm.nih.gov/16580995/)

[Park RJ, et al, (2013) (2013)](https://pubmed.ncbi.nlm.nih.gov/23480558/)

[Scholey R, et al, (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29428298/)

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