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Structure and lipid transport mechanism of a StAR-related domain

Nature Structural Biology volume 7, pages 408–414 (2000)Cite this article

Abstract

The steroidogenic acute regulatory protein (StAR) regulates acute steroidogenesis in the adrenal cortex and gonads by promoting the translocation of cholesterol to the mitochondrial inner membrane where the first step in steriod biosynthesis is catalyzed. StAR-related lipid transfer (START) domains occur in proteins involved in lipid transport and metabolism, signal transduction, and transcriptional regulation. The 2.2 Å resolution crystal structure of the START domain of human MLN64 reported here reveals an α/β fold built around a U-shaped incomplete β-barrel. The interior of the protein encompasses a 26 × 12 × 11 Å hydrophobic tunnel that is large enough to bind a single cholesterol molecule. The StAR and MLN64 START domains bind 1 mole of 14C cholesterol per mole of protein in vitro. Based on the START domain structure and cholesterol binding stoichiometry, it is proposed that StAR acts by shuttling cholesterol molecules one at a time through the intermembrane space of the mitochondrion.

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Figure 1: Representative START domain containing proteins, based on information obtained from the SMART database2.
Figure 2: Cholesterol binding to MLN64 and StAR.
Figure 3: Structure determination.
Figure 4: Overall structure of the START domain of MLN64.
Figure 5: Cutaway view of the molecular surface of the START domain.
Figure 6: Structure based alignment of representative START domain sequences.
Figure 7: Model of cholesterol bound in the START domain tunnel.

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Acknowledgements

We thank D. Stocco, C. Ponting and H. Bernstein for discussions; C. Ogata, R. Abramowitz, Z. Dauter, K. R. Rajashankar, J. Ho, and S. Misra for assistance with data collection at beamlines X4A and X9B, National Synchrotron Light Source, Brookhaven National Laboratories; A. Hickman for comments on the manuscript, and Z. Derewenda for providing expression vectors.

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  1. Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, 20892-0580, Maryland, USA

    Yosuke Tsujishita & James H. Hurley

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  1. Yosuke Tsujishita
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Correspondence to James H. Hurley.

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Tsujishita, Y., Hurley, J. Structure and lipid transport mechanism of a StAR-related domain. Nat Struct Mol Biol 7, 408–414 (2000). https://doi.org/10.1038/75192

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