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This version published online on March 3, 2005
Molecular Endocrinology, doi:10.1210/me.2004-0334
A more recent version of this article appeared on July 1, 2005
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Submitted on August 25, 2004
Accepted on February 22, 2005

Defective calmodulin-mediated nuclear transport of SRY in XY sex reversal

Helena Sim, Kieran Rimmer, Sabine Kelly, Louisa M. Ludbrook, Andrew H.A. Clayton, and Vincent R Harley*

Human Molecular Genetics Laboratory, Prince Henry's Institute of Medical Research, Level 4 Block E, Monash Medical Centre, 246 Clayton Rd, Clayton, Melbourne, Victoria, 3168, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, Victoria, 3010, Australia; Ludwig Institute for Cancer Research, P.O. Box 2008, Parkville, Victoria 3050, Australia

* To whom correspondence should be addressed. E-mail: Vincent.Harley{at}phimr.monash.edu.au.

SRY plays a key role in human sex determination as mutations in SRY can cause XY sex-reversal. While some SRY missense mutations affect DNA binding and bending activities, it is unclear how others contribute to disease. The HMG domain of SRY has two nuclear localization signals (NLS). Sex-reversing mutations in the NLSs affect nuclear import in some patients, associated with defective importin-{beta} binding to the C-terminal NLS (c-NLS), while in others, importin-{beta} recognition is normal, suggesting the existence of an importin-{beta}-independent nuclear import pathway. The SRY N-terminal NLS (n-NLS) binds calmodulin (CaM) in vitro and here we show that this protein interaction is reduced in vivo by calmidazolium (CDZ), a CaM antagonist. In CDZ-treated cells, the dramatic reduction in nuclear entry of SRY and an SRY-c-NLS mutant was not observed for two SRY-n-NLS mutants. Fluorescence spectroscopy studies reveal an unusual conformation of SRY.CaM complexes formed by the two n-NLS mutants. Thus, CaM may be involved directly in SRY nuclear import during gonadal development and disruption of SRY.CaM recognition could underlie XY sex-reversal. Given that the CaM-binding region of SRY is well-conserved among HMG box proteins, CaM-dependent nuclear import may underlie additional disease states.
Key words: SRY • XY sex reversal • nuclear import • calmodulin • HMG box




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