DCTN1

Official Full Name

dynactin subunit 1

Organism

Homo sapiens

GeneID

1639

Background

This gene encodes the largest subunit of dynactin, a macromolecular complex consisting of 10 subunits ranging in size from 22 to 150 kD. Dynactin binds to both microtubules and cytoplasmic dynein. Dynactin is involved in a diverse array of cellular functions, including ER-to-Golgi transport, the centripetal movement of lysosomes and endosomes, spindle formation, chromosome movement, nuclear positioning, and axonogenesis. This subunit interacts with dynein intermediate chain by its domains directly binding to dynein and binds to microtubules via a highly conserved glycine-rich cytoskeleton-associated protein (CAP-Gly) domain in its N-terminus. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. Mutations in this gene cause distal hereditary motor neuronopathy type VIIB (HMN7B) which is also known as distal spinal and bulbar muscular atrophy (dSBMA). [provided by RefSeq, Oct 2008]

Synonyms

P135; DP-150; HMND14; DAP-150;

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Detailed Information

The Dynactin 1 (Dctn1) gene is a crucial player in the molecular mechanisms that underlie various cellular processes, including cell motility, cytokinesis, and endocytosis. This gene encodes a protein that is involved in the formation and function of dynactin, a large macromolecular complex that is composed of multiple subunits.

Structure And Function of Dctn1 Protein

The Dctn1 gene encodes a protein of approximately 60 kDa, which is highly conserved across different species. The protein contains two distinct domains: a N-terminal motor domain and a C-terminal actin-binding domain. The motor domain is responsible for the interaction with microtubules and mediates the retrograde transport of vesicles and organelles. The actin-binding domain interacts with actin filaments, allowing the protein to participate in actin-based motility and cell shape changes.

Role of Dctn1 in Cellular Processes

Dctn1 plays a central role in the regulation of several cellular processes, including:

Cell Motility: Dctn1 is involved in the formation of the leading edge of migrating cells, where it interacts with actin filaments to promote lamellipodia extension. It also participates in the retrograde transport of vesicles and organelles, which is essential for maintaining the functional integrity of the cell.

Cytokinesis: Dctn1 is required for the formation of the central spindle during mitosis, which is responsible for the separation of the daughter cells. It interacts with other cytoskeletal proteins, such as tubulin and actin, to regulate the assembly and function of the central spindle.

Endocytosis: Dctn1 plays a role in endocytosis by interacting with clathrin-coated pits and promoting the internalization of extracellular cargo. This process is essential for cellular signaling, nutrient uptake, and the clearance of pathogens.

Axonal Transport: Dctn1 is involved in the regulation of axonal transport, which is essential for the maintenance of neuronal function and the delivery of neurotransmitters.

Clinical Significance of Dctn1 Dysregulation

Mutations in the Dctn1 gene can lead to defects in cellular processes, which may contribute to various human diseases. For example, mutations in Dctn1 have been associated with neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In addition, dysregulated Dctn1 expression has been detected in various types of cancer, where it promotes cell invasion and metastasis.

Therapeutic Interventions Targeting Dctn1

Given the crucial role of Dctn1 in cellular processes, targeting this gene may provide a potential therapeutic approach for various diseases. Several strategies have been proposed to interfere with Dctn1 function, including:

Small Molecule Inhibitors: Compounds that bind to specific domains of Dctn1, such as the motor or actin-binding domains, can be used to inhibit its activity. These inhibitors may have potential applications in the treatment of diseases characterized by aberrant cell motility or invasion, such as cancer.

siRNA and miRNA-mediated Knockdown: RNA-based therapeutics, such as small interfering RNAs (siRNAs) or microRNAs (miRNAs), can be used to reduce Dctn1 expression. This approach may be suitable for diseases where Dctn1 overexpression is pathogenic, such as cancer or neurodegenerative disorders.

Antibodies and Peptides: Targeting the interaction between Dctn1 and other proteins, such as actin or tubulin, may provide a therapeutic approach for diseases characterized by abnormal cytoskeletal organization. Antibodies or peptides that interfere with these interactions can be developed as potential therapeutics.

References:

Shanmugapriya, Shanmugapriya et al. "Dynactin 1 negatively regulates HIV-1 infection by sequestering the host cofactor CLIP170." Proceedings of the National Academy of Sciences of the United States of America vol. 118,43 (2021): e2102884118. doi:10.1073/pnas.2102884118
Chaaban, Sami, and Andrew P Carter. "Structure of dynein-dynactin on microtubules shows tandem adaptor binding." Nature vol. 610,7930 (2022): 212-216. doi:10.1038/s41586-022-05186-y

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