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Cooperative Nuclear Localization Sequences Lend a Novel Role to the N-Terminal Region of MSH6

Gassman, Natalie R.

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abstract
Human mismatch repair proteins MSH2-MSH6 play an essential role in maintaining genetic stability and preventing disease. While protein functions have been extensively studied, the substantial amino-terminal region (NTR*) of MSH6 that is unique to eukaryotic proteins, has mostly evaded functional characterization. We demonstrate that a cluster of three nuclear localization signals (NLS) in the NTR direct nuclear import. Individual NLSs are capable of partially directing cytoplasmic protein into the nucleus; however only cooperative effects between all three NLSs efficiently transport MSH6 into the nucleus. In striking contrast to yeast and previous assumptions on required heterodimerization, human MSH6 does not determine localization of its heterodimeric partner, MSH2. A cancer-derived mutation localized between two of the three NLS significantly decreases nuclear localization of MSH6, suggesting altered protein localization can contribute to carcinogenesis. These results clarify the pending speculations on the functional role of the NTR in human MSH6 and identify a novel, cooperative nuclear localization signal.
This work was in part supported by a grant from the National Cancer Institute (NCI) (CA101829) and support from the Comprehensive Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or the National Institutes of Health. FRS is partially supported by NCI grant 5R01CA12937. The Zeiss LSM 710 confocal microscope was funded by National Science Foundation MRI award number 0722926. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. (sponsorship)
subject
biophysics
molecular biology
citation
3 (issue)
6 (volume)
contributor
Gassman, Natalie R. (author)
Clodfelter, Jill E. (author)
McCauley, Anita K. (author)
Bonin, Keith (author)
Salsbury, Freddie R., Jr. (author)
Scarpinato, Karin D. (author)
date
2012-08-07T20:23:45Z (accessioned)
2012-08-07T20:23:45Z (available)
2011-03 (issued)
identifier
Gassman NR, Clodfelter JE, McCauley AK, Bonin K, Salsbury FR Jr, et al. (2011) Cooperative Nuclear Localization Sequences Lend a Novel Role to the N-Terminal Region of MSH6. PLoS ONE 6(3): e17907. doi:10.1371/journal.pone.0017907 (citation)
http://hdl.handle.net/10339/37399 (uri)
http://dx.doi.org/10.1371/journal.pone.0017907 (uri)
publisher
PLoS: Public Library of Science
source
PLoS ONE
title
Cooperative Nuclear Localization Sequences Lend a Novel Role to the N-Terminal Region of MSH6
type
Article

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