Journal
STRUCTURE
Volume 23, Issue 7, Pages 1305-1316Publisher
CELL PRESS
DOI: 10.1016/j.str.2015.04.017
Keywords
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Funding
- NIH [GM074846-01A1, T32 GM100836]
- NWO-VIDI grant from the Netherlands Organization for Scientific Research
- Zernike Institute for Advanced Materials
- NCI [P30 CA56036]
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Targeting of ER-synthesized membrane proteins to the inner nuclear membrane (INM) has long been explained by the diffusion-retention model. However, several INM proteins contain non-classical nuclear localization signal (NLS) sequences, which, in a few instances, have been shown to promote importin alpha/beta-and Ran-dependent translocation to the INM. Here, using structural and biochemical methods, we show that yeast INM proteins Heh2 and Src1/Heh1 contain bipartite import sequences that associate intimately with the minor NLSbinding pocket of yeast importin a and unlike classical NLSs efficiently displace the IBB domain in the absence of importin beta. In vivo, the intimate interactions at the minor NLS-binding pocket make the h2NLS highly efficient at recruiting importin alpha at the ER and drive INM localization of endogenous Heh2. Thus, h1/h2NLSs delineate a novel class of super-potent, IBB-like membrane protein NLSs, distinct from classical NLSs found in soluble cargos and of general interest in biology.
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