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bioRxiv · 10.1101/2020.04.14.040436

Molecular basis for the recognition of steroidogenic acute regulatory protein by the 14-3-3 protein family

Tugaeva, K. V.·Titterington, J.·Sotnikov, D. V.·Maksimov, E. G.·Antson, A. A.·Sluchanko, N. N.
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Abstract

Steroidogenesis in adrenals and gonads starts from cholesterol transport to mitochondria by the steroidogenic acute regulatory protein STARD1, containing a mitochondrial import sequence followed by a cholesterol-binding START domain. Although mutations in this protein have been linked to lipoid congenital adrenal hyperplasia, the mechanism of steroidogenesis regulation by the STARD1 remains debatable, hypothetically involving a molten-globule structural transition and interaction with 14-3-3 proteins. We show that, while the isolated START domain does not interact with 14-3-3, interaction is enabled by STARD1 phosphorylation at Ser57, close to the mitochondrial peptide cleavage site. Biochemical analysis of the STARD1 affinity towards 14-3-3 and crystal structures of 14-3-3 complexes with Ser57 and Ser195 phosphopeptides, suggest distinct roles of site-specific phosphorylations in recruiting 14-3-3, to modulate STARD1 activity, processing and import to mitochondria. Phosphorylation at Ser195 creates a unique conditional site, that could only bind to 14-3-3 upon partial unfolding of the START domain.

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Tugaeva, K. V., Titterington, J., Sotnikov, D. V., Maksimov, E. G., Antson, A. A., Sluchanko, N. N.. 2020-04-14. Molecular basis for the recognition of steroidogenic acute regulatory protein by the 14-3-3 protein family. https://doi.org/10.1101/2020.04.14.040436

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