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M704512200v1
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Papers In Press, published online ahead of print December 14, 2007
J. Biol. Chem, 10.1074/jbc.M704512200
Submitted on June 1, 2007
Revised on November 19, 2007
Accepted on December 13, 2007

Serine 88 phosphorylation of the 8 kDa dynein light chain is a molecular switch for its dimerization status and functions

Chunying Song, Wenyu Wen, Suresh K. Rayala, Mingzhi Chen, Jianpeng Ma, Mingjie Zhang, and Rakesh Kumar

MD Anderson Cancer Center, Houston, TX

Corresponding Author: rkumar{at}mdanderson.org

Dynein light chain 1 (DLC1, also known as DYNLL1, LC8, and PIN), a ubiquitously expressed and highly conserved protein, participates in a variety of essential intracellular events. Transition of DLC1 between dimer and monomer forms might play a crucial role in its function. However, the molecular mechanism(s) that controls the transition remains unknown. DLC1 phosphorylation on Ser88 by p21-activated kinase 1 (Pak1), a signaling nodule, promotes mammalian cell survival by regulating its interaction with Bim and Bim’s stablity. Here we discovered that phosphorylation of Ser88, which juxtaposes each other at the interface of DLC dimer, disrupts DLC1 dimer formation and consequently impairs its interaction with Bim. Overexpression of a Ser88 phosphorylation inactive DLC1 mutant in mammary epithelium cells and in a transgenic animal model causes apoptosis and accelerated mammary gland involution, respectively, with increased Bim levels. Structural and biophysical studies suggested that phosphorylation-mimicking mutation leads to dissociation of DLC1 dimer to a pure folded monomer. The phosphorylation-induced DLC1 monomer is incapable of binding to its substrate Bim. These findings reveal a previously unrecognized regulatory mechanism of DLC1 in which the Ser88 phosphorylation acts as a molecular switch for the transition of DLC1 from dimer to monomer, and thereby modulating its interaction with substrates and consequently regulating the functions of DLC1.


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