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MBC in Press, published online ahead of print March 7, 2007
Mol. Biol. Cell 10.1091/mbc.E06-11-1024

A more recent version of this article appeared on May 1, 2007
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Submitted on November 20, 2006
Revised on January 30, 2007
Accepted on February 27, 2007

Conformational Dynamics of the Major Yeast Phosphatidylinositol Transfer Protein Sec14p: Insights into the Mechanisms of Phospholipid Exchange and Diseases of Sec14p-like Protein Deficiencies

Margaret M. Ryan,* Brenda R.S. Temple,{dagger} Scott E. Phillips,* and Vytas A. Bankaitis*

*Department of Cell and Developmental Biology, Lineberger Comprehensive Cancer Research Center; {dagger}R. L. Juliano Structural Bioinformatics Core Facility, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7090

Monitoring Editor: Reid Gilmore

Molecular dynamics simulations coupled with functional analyses of the major yeast phosphatidylinositol/phosphatidylcholine transfer protein Sec14p identify structural elements involved in regulating the ability of Sec14p to execute phospholipid exchange. The molecular dynamics simulations suggest large rigid body motions within the Sec14p molecule accompany closing and opening of an A10/T4/A11 helical gate, and that ‘status-of-closure’ of this helical gate determines access to the Sec14p phospholipid binding cavity. The data also project that conformational dynamics of the helical gate are controlled by a hinge unit (residues F212, Y213, K239, I240, I242) that links to the N- and C-terminal ends of the helical gate, and by a novel gating module (composed of the B1LB2 and A12LT5 substructures) through which conformational information is transduced to the hinge. The 114TDKDGR119 motif of B1LB2 plays an important role in that transduction process. These simulations offer new mechanistic possibilities for an important half-reaction of the Sec14p phospholipid exchange cycle that occurs on membrane surfaces after Sec14p has ejected bound ligand, and is reloading with another phospholipid molecule. These conformational transitions further suggest structural rationales for known disease missense mutations that functionally compromise mammalian members of the Sec14-protein superfamily.

Address correspondence to: Vytas A. Bankaitis (vytas{at}med.unc.edu)




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C. J. Mousley, K. Tyeryar, K. E. Ile, G. Schaaf, R. L. Brost, C. Boone, X. Guan, M. R. Wenk, and V. A. Bankaitis
Trans-Golgi Network and Endosome Dynamics Connect Ceramide Homeostasis with Regulation of the Unfolded Protein Response and TOR Signaling in Yeast
Mol. Biol. Cell, November 1, 2008; 19(11): 4785 - 4803.
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