期刊
JOURNAL OF CELL SCIENCE
卷 128, 期 12, 页码 2287-2301出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.166132
关键词
Telomerase reverse transcriptase; Nuclear localization signal; Importin receptor; Akt; Phosphorylation
类别
资金
- Bio and Medical Technology Development Program of the National Research Foundation - Korean Ministry of Science, ICT, and Future Planning [NRF-2013M3A9B6076413]
- Yonsei University Internal Grant [2014-22-0096]
- National Research Foundation of Korea [NRF-2012R1A2A2A01012830]
Telomeres are essential for chromosome integrity and protection, and their maintenance requires the ribonucleoprotein enzyme telomerase. Previously, we have shown that human telomerase reverse transcriptase (hTERT) contains a bipartite nuclear localization signal (NLS; residues 222-240) that is responsible for nuclear import, and that Akt-mediated phosphorylation of residue S227 is important for efficient nuclear import of hTERT. Here, we show that hTERT binds to importin-alpha proteins through the bipartite NLS and that this heterodimer then forms a complex with importin-beta proteins to interact with the nuclear pore complex. Depletion of individual importin-alpha proteins results in a failure of hTERT nuclear import, and the resulting cytoplasmic hTERT is degraded by ubiquitin-dependent proteolysis. Crystallographic analysis reveals that the bipartite NLS interacts with both the major and minor sites of importin-alpha proteins. We also show that Akt-mediated phosphorylation of S227 increases the binding affinity for importin-alpha proteins and promotes nuclear import of hTERT, thereby resulting in increased telomerase activity. These data provide details of a binding mechanism that enables hTERT to interact with the nuclear import receptors and of the control of the dynamic nuclear transport of hTERT through phosphorylation.
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