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Defective Calmodulin-Mediated Nuclear Transport of the Sex-Determining Region of the Y Chromosome (SRY) in XY Sex Reversal

Human Molecular Genetics Laboratory (H.S., K.R., S.K., L.M.L., V.R.H.), Prince Henry’s Institute of Medical Research, Monash Medical Centre, Clayton, Melbourne, Victoria 3168, Australia; Department of Biochemistry and Molecular Biology (K.R.), University of Melbourne, Victoria 3010, Australia; and Ludwig Institute for Cancer Research (A.H.A.C.), Parkville, Victoria 3050, Australia

Address all correspondence and requests for reprints to: Vincent R. Harley, Prince Henry’s Institute of Medical Research, Level 4 Block E, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. E-mail: Vincent.Harley{at}phimr.monash.edu.au.

The sex-determining region of the Y chromosome (SRY) plays a key role in human sex determination, as mutations in SRY can cause XY sex reversal. Although some SRY missense mutations affect DNA binding and bending activities, it is unclear how others contribute to disease. The high mobility group 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-ß binding to the C-terminal NLS (c-NLS), whereas in others, importin-ß recognition is normal, suggesting the existence of an importin-ß-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, a CaM antagonist. In calmidazolium-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 high mobility group box proteins, CaM-dependent nuclear import may underlie additional disease states.

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