Cytoplasmic dynein is a complex protein found in almost all animal cells, playing a role in maintaining cellular organization and function. It acts as a molecular motor, generating force and movement within the cell. This large complex, typically around 1.5 megadaltons (MDa), is made up of about twelve polypeptide subunits.
The Molecular Motor
Cytoplasmic dynein converts the chemical energy from ATP into mechanical work, moving along cellular tracks called microtubules. This movement is directed towards the “minus-ends” of microtubules, a process known as retrograde transport. Microtubules are dynamic, polar structures with their minus ends located near the cell’s center, often embedded within microtubule organizing centers.
The structure includes two identical “heavy chains,” each weighing approximately 520 kDa. These chains contain the ATPase activity that generates movement and have distinct head and tail domains. The motor domain, located at the C-terminal end of the heavy chain, contains a ring of six AAA+ (ATPases associated with diverse cellular activities) domains.
The heavy chain’s tail domain acts as an assembly platform for other subunits, including two 74 kDa intermediate chains, two 53–59 kDa light intermediate chains, and several light chains. These accessory subunits help anchor dynein to its cargo. The stalk, extending from one of the AAA+ domains, binds to microtubules. As ATP is hydrolyzed, conformational changes within the AAA+ ring alter the affinity of the microtubule-binding stalk, leading to the “walking” motion along the microtubule.
Key Cellular Responsibilities
Cytoplasmic dynein transports materials and organizes cellular structures. It moves various cellular cargoes, including vesicles, organelles like mitochondria and lysosomes, and even viruses, from the outer regions of the cell towards the nucleus. This retrograde transport maintains cellular function and recycles cellular components.
The protein also positions organelles within the cell’s cytoplasm. It places the Golgi complex and other organelles in their locations, which is important for the organized flow of materials and cellular processes.
During cell division, cytoplasmic dynein contributes to the formation and positioning of the mitotic spindle, a structure that separates chromosomes. It is involved in processes such as centrosome separation, pulling on astral microtubules anchored to the cell cortex to align chromosomes in the middle of the cell during metaphase. Dynein also contributes to chromosome segregation during both mitosis and meiosis, ensuring genetic material is correctly distributed to daughter cells.
In nerve cells, cytoplasmic dynein transports materials along axons and dendrites. It is the primary motor for retrograde axonal transport, moving substances from the axon terminals back to the cell body. This includes signaling endosomes for neuronal survival and lysosomes that remove cellular waste. Dynein’s role in neuronal function extends to growth cone mechanics and axon elongation.
When Dynein Goes Wrong
Errors or mutations in cytoplasmic dynein can disrupt cellular processes and lead to health problems. Dysfunction of this motor protein impairs intracellular transport, a characteristic of neurodegenerative diseases. Such disruptions can lead to the accumulation of misfolded protein aggregates in neuronal cytoplasm.
Mutations in the dynein heavy chain, the catalytic component of the complex, are associated with a range of neurodegenerative diseases. These include amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Animal models with dynein dysfunction display motor and neural impairments similar to those seen in human patients.
Beyond neurodegeneration, severe dynein mutations are linked to developmental brain disorders, such as lissencephaly, pachygyria, and polymicrogyria. These conditions involve malformations of cortical development. Defects in dynein-mediated nuclear migration contribute to these early brain development issues.