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Vol. 18, Issue 5, 1928-1942, May 2007

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

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

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

Submitted November 20, 2006; Revised January 30, 2007; Accepted February 27, 2007
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 "state-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, and 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.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

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

Abbreviations used: TTP, -tocopherol transfer protein; OG, -octylglucoside; apf, atomic positional fluctuation; CRALBP, cellular retinaldehyde binding protein; MALDI-TOF, matrix-assisted laser desorption ionization/time of flight; MD, molecular dynamics; NF1, neurofibromin 1; PAGE, polyacrylamide gel electrophoresis; PtdCho, phosphatidylcholine; PtdIns, phosphatidylinositol; rmsd, root mean square deviation; rmsf, root mean square fluctuation.