Abstract
Steroidogenesis in adrenals and gonads starts from cholesterol transport to mitochondria. This is mediated 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 (LCAH), the mechanism of steroidogenesis regulation by STARD1 remains debatable. It has been hypothesized to involve a molten-globule structural transition and interaction with 14-3-3 proteins. In this study, we aimed to address the structural basis for the 14-3-3-STARD1 interaction. We show that, while the isolated START domain does not interact with 14-3-3, this interaction is enabled by STARD1 phosphorylation at Ser57, close to the mitochondrial peptide cleavage site. Biochemical analysis of the STARD1 affinity toward 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 the mitochondria. Phosphorylation at Ser195 creates a unique conditional site that could only bind to 14-3-3 upon partial unfolding of the START domain. Overall, our findings on the interaction between 14-3-3 and STARD1 may have potential clinical implications for patients with LCAH.
Highlights
Steroid hormones control many processes including metabolism, immune functions and sex differentiation
STARD1 was first identified as phosphoprotein upgerulated in the acute phase of steroidogenesis in cAMP-stimulated adrenal cortex, corpus luteum and Leydig cells [4, 5, 34, 35]
The first motif is located within the N-terminal part of the protein, upstream of the START domain, whereas the second and the third motifs reside inside the START domain (Fig. 1A)
Summary
Steroid hormones control many processes including metabolism, immune functions and sex differentiation. Steroidogenesis in adrenals and gonads is kinetically limited by cholesterol transport to the inner mitochondrial membrane (IMM), where the enzymatic conversion of cholesterol into pregnenolone takes place [1]. This bottleneck stage of steroidogenesis is largely dependent on the cAMP-dependent de novo synthesis and function of the steroidogenic acute regulatory protein StAR, referred to as STARD1 [2,3,4,5]. Deletion or knockout of the star gene arrests steroidogenesis leading to the accumulation of cholesterol-enriched lipid droplets in the cytoplasm of steroidogenic cells [6, 7]. A range of STARD1 mutations impair its function leading to autosomal recessive disorders called lipoid congenital adrenal hyperplasias (LCAH) [6]. The critical role of STARD1 in steroidogenesis is underlined by the ability of the wild-type STARD1 transgene to completely rescue the lethal STARD1-/- phenotype in knockout mice [8, 9]
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