The dynein and myosin V motor complexes are multi-protein structures that function to transport molecules and organelles within the cell. DLC (dynein light-chain) proteins, found as components of both dynein and myosin V motor complexes, connect the complexes to their cargoes. One of the roles of these motor complexes is to selectively sequester the pro-apoptotic ‘BH3-only’ (Bcl-2 homology 3-only) proteins, Bim (Bcl-2-interacting mediator of cell death) and Bmf (Bcl-2-modifying factor), and so regulate their cell death-inducing function. In vivo DLC2 is found exclusively as a component of the myosin V motor complex and Bmf binds DLC2 selectively. On the other hand, Bim interacts with DLC1 (LC8), an integral component of the dynein motor complex. The two DLCs share 93% sequence identity yet show unambiguous in vivo specificity for their respective BH3-only ligands. To investigate this specificity the three-dimensional solution structure of DLC2 was elucidated using NMR spectroscopy. In vitro structural and mutagenesis studies show that Bmf and Bim have identical binding characteristics to recombinant DLC2 or DLC1. Thus the selectivity shown by Bmf and Bim for binding DLC1 or DLC2, respectively, does not reside in their DLC-binding domains. Remarkably, mutational analysis of DLC1 and DLC2 indicates that a single surface residue (residue 41) determines the specific localization of DLCs with their respective motor complexes. These results suggest a molecular mechanism for the specific compartmentalization of DLCs and their pro-apoptotic cargoes and implicate other protein(s) in defining the specificity between the cargoes and the DLC proteins.
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February 2004
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Research Article|
February 01 2004
Localization of dynein light chains 1 and 2 and their pro-apoptotic ligands
Catherine L. DAY;
Catherine L. DAY
*Department of Biochemistry, University of Otago, Dunedin, New Zealand
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Hamsa PUTHALAKATH;
Hamsa PUTHALAKATH
†The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3050, Australia
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Gretchen SKEA;
Gretchen SKEA
*Department of Biochemistry, University of Otago, Dunedin, New Zealand
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Andreas STRASSER;
Andreas STRASSER
†The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3050, Australia
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Igor BARSUKOV;
Igor BARSUKOV
‡Biological NMR Centre, University of Leicester, Leicester, U.K.
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Lu-Yun LIAN;
Lu-Yun LIAN
§Department of Biomolecular Sciences, UMIST, Manchester, U.K.
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David C. S. HUANG;
David C. S. HUANG
†The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3050, Australia
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Mark G. HINDS
Mark G. HINDS
1
†The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, VIC 3050, Australia
1To whom correspondence should be addressed (e-mail mhinds@wehi.edu.au).
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Publisher: Portland Press Ltd
Received:
August 15 2003
Revision Received:
October 10 2003
Accepted:
October 15 2003
Accepted Manuscript online:
October 15 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2004
2004
Biochem J (2004) 377 (3): 597–605.
Article history
Received:
August 15 2003
Revision Received:
October 10 2003
Accepted:
October 15 2003
Accepted Manuscript online:
October 15 2003
Citation
Catherine L. DAY, Hamsa PUTHALAKATH, Gretchen SKEA, Andreas STRASSER, Igor BARSUKOV, Lu-Yun LIAN, David C. S. HUANG, Mark G. HINDS; Localization of dynein light chains 1 and 2 and their pro-apoptotic ligands. Biochem J 1 February 2004; 377 (3): 597–605. doi: https://doi.org/10.1042/bj20031251
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