LIS1 a Critical Regulator of Dynein Complex Formation and Function

Background - Dynein Complex Structure

Movement of cargo towards the minus-end of microtubules is performed by cytoplasmic dynein-1 that is in a complex with the regulatory factor dynactin and cargo adaptor proteins^{(reviewed in 1)}.  Mutations in dynein, its regulatory proteins, and cargo adaptor proteins have all been associated with severe neurologic disorders, and recent studies showed that the impact the mutation has on the molecular pathology directly correlates with the severity of the neurologic disease². DDA complexes are very large, which has traditionally made it difficult to study, and deciphering critical functions each component has on the complex has also proven challenging.  The advancement in single-molecule imaging and structural studies via cryo-electron microscopy (cryo-EM) produced a flurry of information regarding the DDA complex structure and function. In 2014, two studies showed that mammalian dynein had minimal movement along microtubules on its own, which was striking relative to much of the earlier studies that were commonly performed with yeast dynein³ or on solid surfaces (glass coverslips)⁴; importantly, upon mammalian dynein binding to mammalian dynactin and cargo adaptors, significant movement was observed^5,6.  Cryo-EM studies were performed to identify the autoinhibitory state of dynein, which is known as the phi particle⁷. In 2018, the Carter group utilized elegant Cryo-EM studies to show that dynactin can bind one or two dynein proteins depending on the adaptor protein that is in the DDA complex; importantly, the double-bound dynein had much higher force and speed providing insight into how different adaptors produce profound regulatory effects on cargo movement⁸.  More recently, it was shown that DDA complexes with two dynein proteins contained two adaptors, which were asymmetrically bound to dynactin⁹.  Collectively, these and other studies point to a DDA complex that is highly regulated and involves multiple precise interactions for proper function.  In addition to understanding the structure and function of the DDA complex, there has been significant work in understanding how regulatory factors like the LIS1 protein affect dynein motor movement. This newsletter will discuss some of these recent findings and how they expand our understanding of LIS1 in the DDA complex and beyond.

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Also Included in this Newsletter:

• - Tubulin and Microtubule Tools
• - Related Publications