DCTN1

DCTN1 encodes p150Glued, the largest subunit of dynactin, the multiprotein complex that activates cytoplasmic dynein-1. p150Glued forms, with DCTN2 and DCTN3, the shoulder of the Arp1-filament-based dynactin complex and projects a long coiled-coil arm ending in an N-terminal CAP-Gly and basic domain. Through these regions it binds dynein intermediate chain, microtubules (preferentially tyrosinated) and plus-end tracking proteins EB1 and CLIP-170, so that dynactin, together with a cargo adaptor such as BICD2 or HOOK3, converts dynein into an ultra-processive minus-end-directed motor and loads it at microtubule plus ends. Dynein-dynactin transports vesicles, endosomes, lysosomes, retromer carriers and other organelles, drives retrograde axonal transport, and pulls on the nuclear envelope in nuclear positioning, neuronal nucleokinesis and prophase nuclear envelope breakdown. In mitosis p150Glued localizes to kinetochores, spindle poles and the cell cortex, where cortical dynein-dynactin positions and orients the spindle. A separate centrosomal pool at mother-centriole subdistal appendages anchors microtubules and supports centriole cohesion and primary cilium formation. The neuron-enriched full-length isoform (with CAP-Gly domain) also acts directly on microtubules, promoting nucleation and suppressing catastrophe. CAP-Gly domain mutations cause Perry syndrome and distal hereditary motor neuronopathy, and DCTN1 variants are associated with ALS susceptibility.

Disorders

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