Abstract
Dynactin is a dynein-regulating protein that increases the processivity of dynein movement on microtubules. Recent studies have shown that a tripartite complex of dynein–dynactin–Bicaudal D2 is essential for highly processive movement. To elucidate the regulation of dynein motility by dynactin, we focused on two isoforms (A and B) of dynactin 1 (DCTN1), the largest subunit of dynactin that contains both microtubule- and dynein-binding domains. The only difference between the primary structures of the two isoforms is that DCTN1B lacks the K-rich domain, a cluster of basic residues. We measured dynein motility by single molecule observation of recombinant dynein and dynactin. Whereas the tripartite complex containing DCTN1A exhibited highly processive movement, the complex containing DCTN1B dissociated from microtubules with no apparent processive movement. This inhibitory effect of DCTN1B was caused by reductions of the microtubule-binding affinities of both dynein and dynactin, which was attributed to the coiled-coil 1 domain of DCTN1. In DCTN1A, the K-rich domain antagonized these inhibitory effects. Therefore, dynactin has two antagonistic domains and promotes or suppresses dynein motility to accomplish correct localization and functions of dynein within a cell.
Highlights
Dynactin is a very large multi-subunit complex that links dynein with its cargo and is known as a cytoplasmic dynein modulator by binding dynein to specific vesicles or organelles [1,2,3]
To investigate whether dynactin 1 (DCTN1) isoforms influence the highly processive movement of dynein–dynactin– BICD2 (DDB) complexes, we observed the behavior of DDB complexes with different DCTN1 isoforms (1A and 1B) by total internal reflection fluorescence (TIRF) microscopy (Fig 1)
We found that dynactin has two agonistic regulatory domains (CC1 and K-rich domains) and exerts opposing effects on dynein motility depending on the DCTN1 isoform
Summary
Dynactin is a very large multi-subunit complex that links dynein with its cargo and is known as a cytoplasmic dynein modulator by binding dynein to specific vesicles or organelles [1,2,3]. Cytoplasmic dynein is a minus end-directed multi-subunit microtubule motor protein [4]. Dynactin is involved in many cellular functions, including vesicle transport [2,5], organelle positioning [6,7], spindle assembly [8] and microtubule plus end localization [9,10,11] with dynein. Dynactin abnormalities cause several diseases, including Perry syndrome [12,13] and amyotrophic lateral sclerosis [14,15]. Correct localization of the DD complex is important for maintenance of cellular functions
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