Shared functions of plant and mammalian StAR-related lipid transfer (START) domains in modulating transcription factor activity

Abstract

BackgroundSteroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domains were first identified from mammalian proteins that bind lipid/sterol ligands via a hydrophobic pocket. In plants, predicted START domains are predominantly found in homeodomain leucine zipper (HD-Zip) transcription factors that are master regulators of cell-type differentiation in development. Here we utilized studies of Arabidopsis in parallel with heterologous expression of START domains in yeast to investigate the hypothesis that START domains are versatile ligand-binding motifs that can modulate transcription factor activity.ResultsOur results show that deletion of the START domain from Arabidopsis Glabra2 (GL2), a representative HD-Zip transcription factor involved in differentiation of the epidermis, results in a complete loss-of-function phenotype, although the protein is correctly localized to the nucleus. Despite low sequence similarly, the mammalian START domain from StAR can functionally replace the HD-Zip-derived START domain. Embedding the START domain within a synthetic transcription factor in yeast, we found that several mammalian START domains from StAR, MLN64 and PCTP stimulated transcription factor activity, as did START domains from two Arabidopsis HD-Zip transcription factors. Mutation of ligand-binding residues within StAR START reduced this activity, consistent with the yeast assay monitoring ligand-binding. The D182L missense mutation in StAR START was shown to affect GL2 transcription factor activity in maintenance of the leaf trichome cell fate. Analysis of in vivo protein–metabolite interactions by mass spectrometry provided direct evidence for analogous lipid-binding activity in mammalian and plant START domains in the yeast system. Structural modeling predicted similar sized ligand-binding cavities of a subset of plant START domains in comparison to mammalian counterparts.ConclusionsThe START domain is required for transcription factor activity in HD-Zip proteins from plants, although it is not strictly necessary for the protein’s nuclear localization. START domains from both mammals and plants are modular in that they can bind lipid ligands to regulate transcription factor function in a yeast system. The data provide evidence for an evolutionarily conserved mechanism by which lipid metabolites can orchestrate transcription. We propose a model in which the START domain is used by both plants and mammals to regulate transcription factor activity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-014-0070-8) contains supplementary material, which is available to authorized users.

ATML1 activity is restricted to the outermost cells of the embryo through post-transcriptional repressions

“…To further gain the mechanical insights of the post-transcriptional repression of ATML1, we performed domain deletion analyses. Among the four domains of ATML1, we focused on ZLZ and START domains because of their potential to interact with other regulatory molecules: the ZLZ domain is known as a dimerization motif and the START domain is predicted as a lipid/sterol-binding domain (Schrick et al, 2014). To assess the role of each domain in ATML1 localization, we generated transgenic lines that expressed 3xGFP-ATML1 fusion genes, with or without deletion of ZLZ or START, under the control of the ATML1 promoter ( proML1-3xGFP-ML1, proML1-3xGFP-ML1ΔZLZ and proML1-3xGFP-ML1ΔSTART).…”

“…ZLZ and START domains were shown to interact with other molecules or act as target sites for post-translational modification (Tron et al, 2002;Schrick et al, 2014). It has been reported that the START domain of ATML1 stimulated transcription factor activity in yeast in response to increased sterol biosynthesis (Schrick et al, 2014). Therefore, HD-ZIP class IV START domains may be involved in post-translational activation of transcription factors.…”

Comparative Transcriptomic Analyses by RNA-seq to Elucidate Differentially Expressed Genes in the Muscle of Korean Thoroughbred Horses

“…Steroidogenic acute regulatory protein (STAR) related to lipid transfer plays a key role in the acute regulation of steroid hormone synthesis by enhancing the conversion of cholesterol into pregnenolone [25]. There is evidence that cholesterol plays a direct role in inflammation which promotes muscle building and strength [26][27][28].…”

Author response: A new family of StART domain proteins at membrane contact sites has a role in ER-PM sterol transport

“…In contrast, PITPα present in the same experiment extracted phosphatidylcholine (PC) and phosphatidylinositol (PI) but not cholesterol (data not shown). Therefore, the lack of recovery of the major phospholipids, including PC, PI, phosphatidylserine (PS) and phosphatidylethanolamine (PE), by Lam4S2 indicates that if it does bind phospholipids non-specifically (Schrick et al, 2014), such binding can only be weak (Kd >100 μM).…”