DCTN1

DCTN1 Full Name

dynactin 1

DCTN1 Introduction

DCTN1 encodes p150(glued), the largest subunit of dynactin, a multisubunit complex that is essential for the function of cytoplasmic dynein, the molecular motor that transports cargo toward the minus ends of microtubules. Intracellular transport is fundamental to cell biology: dynein moves organelles, vesicles, mRNAs, and proteins from the periphery of the cell toward the center, and it drives the movements of chromosomes, the mitotic spindle, and primary cilia. Dynactin is the obligatory partner of dynein: it increases the processivity of the motor, links it to its many cargos, and recruits it to the microtubules along which it travels, and p150(glued) is the subunit that carries out several of these key functions. The N-terminal region of p150(glued) contains a CAP-Gly domain that binds directly to microtubules and to the microtubule-plus-end tracking proteins that load cargo onto the motor, while other regions of the protein connect dynactin to the dynein motor itself and to the myriad adaptors that select specific cargos. Given this central role, it is not surprising that mutations in DCTN1 cause human disease: dominant mutations in the CAP-Gly domain cause Perry syndrome, a rare neurodegenerative disorder combining parkinsonism, depression, weight loss, and respiratory failure, and other variants have been linked to motor neuron disease and to frontotemporal dementia. The study of dynactin has thus provided fundamental insights into how cells organize their interior and into the mechanisms of neurodegenerative disease.

Figure 1. The structure of DCTN1.

Subunit Architecture and Microtubule-Binding Function
Dynactin is a large complex built from multiple subunits, and p150(glued), encoded by DCTN1, is its largest and best-characterized component.
The N-terminus of p150(glued) contains a CAP-Gly domain, a glycine-rich module that binds the acidic C-terminal tails of tubulin on the microtubule surface.
Immediately following the CAP-Gly domain are basic and coiled-coil regions that mediate dimerization of p150(glued) and its interaction with the p50/dynamitin subunit, through which the entire dynactin complex is assembled.
p150(glued) binds directly to the dynein intermediate chain, coupling the dynactin cargo-binding machinery to the dynein motor, and it also interacts with the coiled-coil protein that stabilizes the dynein-dynactin interaction.
The DCTN1 gene is located on human chromosome 2, and alternative splicing produces isoforms with or without the CAP-Gly domain, generating variants with different microtubule-binding properties.
Through its CAP-Gly domain, p150(glued) also binds the microtubule-plus-end tracking protein EB1 and the motor that transports cargos toward the plus end, kinesin, placing dynactin at the interface between the two major microtubule motors.
The long coiled-coil of p150(glued) projects from the dynactin complex, giving it the appearance of a shoulder and arm that reach toward the microtubule and toward cargos.

Dynein-Mediated Transport, Perry Syndrome, and Neurodegeneration
Dynactin is required for essentially all dynein-mediated transport, and p150(glued) contributes both by enhancing the processivity of the motor and by connecting it to the diverse adaptors that recognize different cargos.
In neurons, dynein-dynactin transports organelles, autophagosomes, and signaling endosomes along axons, and disruption of this transport is a recurring theme in neurodegenerative disease.
Dominant mutations in the CAP-Gly domain of p150(glued) cause Perry syndrome, an autosomal dominant disorder characterized by parkinsonism that does not respond well to levodopa, together with depression, severe weight loss, and central hypoventilation.
Postmortem studies of Perry syndrome show degeneration of the substantia nigra and other affected brain regions, and the disease-causing mutations impair the microtubule-binding or cargo-recognition functions of the protein.
Other DCTN1 mutations have been associated with amyotrophic lateral sclerosis, distal hereditary motor neuropathy, and frontotemporal dementia, broadening the clinical spectrum of dynactin dysfunction.
Because the dynein-dynactin machinery is also required for the autophagy that clears toxic protein aggregates, defects in p150(glued) may contribute to neurodegeneration both through impaired transport and through failed protein quality control, and the complex is being studied as a target for therapies that enhance axonal transport.

Alternate Names for DCTN1

DCTN1; dynactin 1; dynactin 1 (p150, Glued (Drosophila) homolog); dynactin subunit 1; p150 glued homolog (Drosophila); 150 kDa dynein-associated polypeptide; dynactin 1 (p150, glued homolog, Drosophila); P135; DP-150; DAP-150;