Interaction of a putative BH3 domain of clusterin with anti-apoptotic Bcl-2 family proteins as revealed by NMR spectroscopy |
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Authors: | Lee Dong-Hwa Ha Ji-Hyang Kim Yul Bae Kwang-Hee Park Jae-Yong Choi Wan Sung Yoon Ho Sup Park Sung Goo Park Byoung Chul Yi Gwan-Su Chi Seung-Wook |
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Institution: | aMedical Proteomics Research Center, KRIBB, Daejeon 305-806, Republic of Korea;bDepartment of Bio and Brain Engineering, KAIST, Daejeon 305-701, Republic of Korea;cDepartment of Physiology, Institute of Health Science, School of Medicine, Gyeongsang National University, Jinju, Gyeongnam 660-751, Republic of Korea;dDepartment of Anatomy and Neurobiology, Institute of Health Science, School of Medicine, Gyeongsang National University, Jinju, Gyeongnam 660-751, Republic of Korea;eDivision of Structural and Computational Biology, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637511, Singapore |
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Abstract: | Clusterin (CLU) is a multifunctional glycoprotein that is overexpressed in prostate and breast cancers. Although CLU is known to be involved in the regulation of apoptosis and cell survival, the precise molecular mechanism underlying the pro-apoptotic function of nuclear CLU (nCLU) remains unclear. In this study, we identified a conserved BH3 motif in C-terminal coiled coil (CC2) region of nCLU by sequence analysis and characterized the molecular interaction of the putative nCLU BH3 domain with anti-apoptotic Bcl-2 family proteins by nuclear magnetic resonance (NMR) spectroscopy. The chemical shift perturbation data demonstrated that the nCLU BH3 domain binds to pro-apoptotic BH3 peptide-binding grooves in both Bcl-XL and Bcl-2. A structural model of the Bcl-XL/nCLU BH3 peptide complex reveals that the binding mode is remarkably similar to those of other Bcl-XL/BH3 peptide complexes. In addition, mutational analysis confirmed that Leu323 and Asp328 of nCLU BH3 domain, absolutely conserved in the BH3 motifs of BH3-only protein family, are critical for binding to Bcl-XL. Taken altogether, our results suggest a molecular basis for the pro-apoptotic function of nCLU by elucidating the residue specific interactions of the BH3 motif in nCLU with anti-apoptotic Bcl-2 family proteins. |
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Keywords: | Clusterin Apoptosis BH3 domain NMR Bcl-2 family protein |
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