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Lys63-linked ubiquitin chain adopts multiple conformational states for specific target recognition.

Liu Z, Gong Z, Jiang WX, Yang J, Zhu WK, Guo DC, Zhang WP, Liu ML, Tang C - Elife (2015)

Bottom Line: Free or bound to ligands, polyubiquitins are found in different arrangements of ubiquitin subunits.A point mutation that shifts the equilibrium between the different states modulates the binding affinities towards K63-Ub2 ligands.This conformational selection mechanism at the quaternary level may be used by polyubiquitins of different lengths and linkages for target recognition.

View Article: PubMed Central - PubMed

Affiliation: CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics, Wuhan Institute of Physics and Mathematics of the Chinese Academy of Sciences, Wuhan, China.

ABSTRACT
A polyubiquitin comprises multiple covalently linked ubiquitins and recognizes myriad targets. Free or bound to ligands, polyubiquitins are found in different arrangements of ubiquitin subunits. To understand the structural basis for polyubiquitin quaternary plasticity and to explore the target recognition mechanism, we characterize the conformational space of Lys63-linked diubiquitin (K63-Ub2). Refining against inter-subunit paramagnetic NMR data, we show that free K63-Ub2 exists as a dynamic ensemble comprising multiple closed and open quaternary states. The quaternary dynamics enables K63-Ub2 to be specifically recognized in a variety of signaling pathways. When binding to a target protein, one of the preexisting quaternary states is selected and stabilized. A point mutation that shifts the equilibrium between the different states modulates the binding affinities towards K63-Ub2 ligands. This conformational selection mechanism at the quaternary level may be used by polyubiquitins of different lengths and linkages for target recognition.

No MeSH data available.


Related in: MedlinePlus

Proposed mechanism for K63-Ub2 signaling.In the absence of a ligand, K63-Ub2 alternates between an open and two closed states. A specific ligand can be accommodated and bound to one of the three preexisting conformations, eliciting the downstream signal.DOI:http://dx.doi.org/10.7554/eLife.05767.027
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fig8: Proposed mechanism for K63-Ub2 signaling.In the absence of a ligand, K63-Ub2 alternates between an open and two closed states. A specific ligand can be accommodated and bound to one of the three preexisting conformations, eliciting the downstream signal.DOI:http://dx.doi.org/10.7554/eLife.05767.027

Mentions: Together, our ensemble structural refinement and mutational analysis revealed that ligand-free K63-Ub2 adopts at least three conformational states, including one open state and two closed states, each of which can accommodate cognate ligands. Closed compact structures have been reported for ligand-free diubiquitins with Lys48 (Cook et al., 1992), Lys11 (Matsumoto et al., 2010; Castaneda et al., 2013), Lys29, and Lys33 (Kristariyanto et al., 2015; Michel et al., 2015) linkages. These structures are different from the C1 or C2 closed-state conformations of K63-Ub2, and therefore are involved in different functions. As such, a covalent ubiquitin linkage dictates how the two subunits non-covalently interact with each other in a diubiquitin, and resulting quaternary arrangements encode specific cell signals. For K63-Ub2, the open state recognizes tUIM of Rap80 and is involved in DNA damage repair, the C2 closed state recognizes the NZF domain of TAK1 binding proteins and is involved in the activation of NF-κB signaling, while the C1 state recognizes the ZnF4 domain of A20 and is involved in the termination of NF-κB signaling pathways (Figure 8). Constructed from repeating units of diubiquitins, a polyubiquitin should exist in a combination of quaternary structures of the diubiquitins and participate in diverse functions.10.7554/eLife.05767.027Figure 8.Proposed mechanism for K63-Ub2 signaling.


Lys63-linked ubiquitin chain adopts multiple conformational states for specific target recognition.

Liu Z, Gong Z, Jiang WX, Yang J, Zhu WK, Guo DC, Zhang WP, Liu ML, Tang C - Elife (2015)

Proposed mechanism for K63-Ub2 signaling.In the absence of a ligand, K63-Ub2 alternates between an open and two closed states. A specific ligand can be accommodated and bound to one of the three preexisting conformations, eliciting the downstream signal.DOI:http://dx.doi.org/10.7554/eLife.05767.027
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4507786&req=5

fig8: Proposed mechanism for K63-Ub2 signaling.In the absence of a ligand, K63-Ub2 alternates between an open and two closed states. A specific ligand can be accommodated and bound to one of the three preexisting conformations, eliciting the downstream signal.DOI:http://dx.doi.org/10.7554/eLife.05767.027
Mentions: Together, our ensemble structural refinement and mutational analysis revealed that ligand-free K63-Ub2 adopts at least three conformational states, including one open state and two closed states, each of which can accommodate cognate ligands. Closed compact structures have been reported for ligand-free diubiquitins with Lys48 (Cook et al., 1992), Lys11 (Matsumoto et al., 2010; Castaneda et al., 2013), Lys29, and Lys33 (Kristariyanto et al., 2015; Michel et al., 2015) linkages. These structures are different from the C1 or C2 closed-state conformations of K63-Ub2, and therefore are involved in different functions. As such, a covalent ubiquitin linkage dictates how the two subunits non-covalently interact with each other in a diubiquitin, and resulting quaternary arrangements encode specific cell signals. For K63-Ub2, the open state recognizes tUIM of Rap80 and is involved in DNA damage repair, the C2 closed state recognizes the NZF domain of TAK1 binding proteins and is involved in the activation of NF-κB signaling, while the C1 state recognizes the ZnF4 domain of A20 and is involved in the termination of NF-κB signaling pathways (Figure 8). Constructed from repeating units of diubiquitins, a polyubiquitin should exist in a combination of quaternary structures of the diubiquitins and participate in diverse functions.10.7554/eLife.05767.027Figure 8.Proposed mechanism for K63-Ub2 signaling.

Bottom Line: Free or bound to ligands, polyubiquitins are found in different arrangements of ubiquitin subunits.A point mutation that shifts the equilibrium between the different states modulates the binding affinities towards K63-Ub2 ligands.This conformational selection mechanism at the quaternary level may be used by polyubiquitins of different lengths and linkages for target recognition.

View Article: PubMed Central - PubMed

Affiliation: CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic Molecular Physics, Wuhan Institute of Physics and Mathematics of the Chinese Academy of Sciences, Wuhan, China.

ABSTRACT
A polyubiquitin comprises multiple covalently linked ubiquitins and recognizes myriad targets. Free or bound to ligands, polyubiquitins are found in different arrangements of ubiquitin subunits. To understand the structural basis for polyubiquitin quaternary plasticity and to explore the target recognition mechanism, we characterize the conformational space of Lys63-linked diubiquitin (K63-Ub2). Refining against inter-subunit paramagnetic NMR data, we show that free K63-Ub2 exists as a dynamic ensemble comprising multiple closed and open quaternary states. The quaternary dynamics enables K63-Ub2 to be specifically recognized in a variety of signaling pathways. When binding to a target protein, one of the preexisting quaternary states is selected and stabilized. A point mutation that shifts the equilibrium between the different states modulates the binding affinities towards K63-Ub2 ligands. This conformational selection mechanism at the quaternary level may be used by polyubiquitins of different lengths and linkages for target recognition.

No MeSH data available.


Related in: MedlinePlus