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J Biol Chem. 2020 Mar 5. pii: jbc.RA119.011653. doi: 10.1074/jbc.RA119.011653. [Epub ahead of print]

The dynein light chain 8 (LC8) binds "in-register" to multivalent intrinsically disordered partners.

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Oregon State University, United States.
Chemistry and Biochemistry, University of Oregon, United States.
University of Oregon, United States.
Biochemistry and Biophysics, Oregon State University, United States.


Dynein light chain 8 (LC8) interacts with intrinsically disordered proteins (IDPs) and influences a wide range of biological processes. It is becoming apparent that among the numerous IDPs that interact with LC8, many contain multiple LC8-binding sites. Although it is established that LC8 forms parallel IDP duplexes with some partners, such as nucleoporin Nup159 and dynein intermediate chain, the molecular details of these interactions, and LC8's interactions with other diverse partners, remain largely uncharacterized. LC8 dimers could bind in either a paired "in-register" or in a heterogeneous "off-register" manner to any of the available sites on a multivalent partner. Here, using NMR chemical shift perturbation, analytical ultracentrifugation, and native electrospray ionization MS, we show that LC8 forms a stable "in-register" complex when bound to an IDP domain of the multivalent regulatory protein ATM/ATR-substrate CHK2-interacting zinc finger protein (ASCIZ). Using saturation transfer difference NMR, we demonstrate that at sub-stoichiometric LC8 concentrations, the IDP domain preferentially binds to one of the three LC8 recognition motifs, showing for the first time that the binding process is "in-register." Further, the dynamic behavior for the three sites and the size of the fully bound complex confirmed an "in-register" complex. Dynamics measurements also revealed that coupling between sites is dependent on the linker length separating these sites. These results identify linker length and motif specificity as drivers of "in-register" binding in the multivalent LC8/IDP complex assembly.


LC8; analytical ultracentrifugation; intrinsically disordered protein; multivalency; native mass spectrometry; nuclear magnetic resonance (NMR); protein assembly; protein dynamic

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