Give lipids a START: the StAR-related lipid transfer (START) domain in mammals

Abstract

The steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain is a protein module of ∼210 residues that binds lipids, including sterols. Fifteen mammalian proteins, STARD1-STARD15, possess a START domain and these can be grouped into six subfamilies. Cholesterol, 25-hydroxycholesterol, phosphatidylcholine, phosphatidylethanolamine and ceramides are ligands for STARD1/STARD3/STARD5, STARD5, STARD2/STARD10, STARD10 and STARD11, respectively. The lipids or sterols bound by the remaining 9 START proteins are unknown. Recent studies show that the C-terminal end of the domain plays a fundamental role, forming a lid over a deep lipid-binding pocket that shields the ligand from the external environment. The START domain can be regarded as a lipid-exchange and/or a lipid-sensing domain. Mammalian START proteins have diverse expression patterns and can be found free in the cytoplasm, attached to membranes or in the nucleus. They appear to function in a variety of distinct physiological processes, such as lipid transfer between intracellular compartments, lipid metabolism and modulation of signaling events. Mutation or misexpression of START proteins is linked to pathological processes, including genetic disorders, autoimmune disease and cancer.

Cholesterol transport from late endosomes to the Golgi regulates t-SNARE trafficking, assembly, and function

“…Although increased t-SNARE endocytosis in AnxA6-overexpressing cells cannot be completely ruled out as contributing to the phenotype observed, the ability of AnxA6 to impact on SNARE localization and functioning is probably linked to its association with late endosomes, which plays a crucial role in cholesterol trafficking and homeostasis. Late endosomes are a sorting station and are capable of exporting cholesterol via vesicular (Maxfield and Tabas, 2005; Urano et al , 2008) and nonvesicular (protein-mediated) transport mechanisms involving NPC1 (Garver and Heidenreich, 2002) and cytoplasmic sterol-binding proteins (e.g., oxysterol-binding protein/OSBP-related proteins [OSBP/ORPs], ORP5; Ngo et al , 2010; Du et al , 2011) or through StAR-related lipid transfer domain (START)-domain proteins (Soccio and Breslow, 2003; Alpy and Tomasetto, 2005; Ikonen, 2008). In CHO-A6 cells, cholesterol accumulates in late endosomes, probably due to AnxA6 interference with NPC1 activity.…”

Nonvesicular Lipid Transfer from the Endoplasmic Reticulum

“…Sterol-transfer proteins may also mediate nonvesicular transport of sterols in yeast and mammals. Several candidates might be involved, including OSBP and ORPs in mammals and Osh (OSBP homologs) proteins in budding yeast (Lehto and Olkkonen 2003) StAR, the prototype for the START proteins, plays a crucial role in steroidogenesis by facilitating the delivery of cholesterol from the outer to the inner mitochondrial membrane, where the first step in steroid biosynthesis is catalyzed (Alpy and Tomasetto 2005). It can transfer cholesterol between membranes in vitro, and robustly transfers cholesterol within steroidogenic cells ( 400 molecules of cholesterol into the mitochondria per minute [Ikonen and Jansen 2008]).…”

Effects of Structure of Rho GTPase-activating Protein DLC-1 on Cell Morphology and Migration

“…The ϳ210-amino acid START domains are found in 15 distinct proteins, either alone (e.g. STARD4) or as with DLC-1, associated with other protein domains (19). Some have been shown to bind lipids or sterols, and START domain-containing proteins exhibit very distinct subcellular locations.…”