SMP-domain proteins at membrane contact sites: Structure and function

Abstract

SMP-domains are found in proteins that localize to membrane contact sites. Elucidation of the properties of these proteins gives clues as to the molecular bases underlying processes that occur at such sites. Described here are recent discoveries concerning the structure, function, and regulation of the Extended-Synaptotagmin proteins and ERMES complex subunits, SMP-domain proteins at endoplasmic reticulum (ER)- plasma membrane and ER-mitochondrial contacts, respectively. They act as tethers contributing to the architecture of these sites and as lipid transporters that convey glycerolipids between apposed membranes.

Emerging Roles for the Lysosome in Lipid Metabolism

“…Non-vesicular trafficking is mediated by several classes of lipid-binding proteins that localize at sites of physical proximity between different organelles both in mammalian and yeast cells (reviewed in (Daniele and Schiaffino, 2016, Lahiri et al, 2015, Phillips and Voeltz, 2016). These protein families derive their names from characteristic lipid-binding domains they harbor, which include the Oxysterol Binding Protein (OSBP)-Related Proteins (ORPs, also known as Osh proteins in yeast) (Mesmin et al, 2013a, Phillips and Voeltz, 2016), the ‘Steroidogenic Acute Regulatory Protein Related Lipid Transfer’ (STARTs) (Alpy and Tomasetto, 2014), the related VAD1 Analog of Star Related Lipid Transfer (VASt) and the Synaptotagmin-like Mitochondrial Lipid Binding Protein (SMP) (Reinisch and De Camilli, 2016). With the exception of the START proteins, which are only found in metazoans, these domains are present in all eukaryotes.…”

The Extended-Synaptotagmins

“…The predicted similarity of the SMP domain to lipid harboring protein modules of the TULIP (tubular lipid-binding) superfamily was the first clue suggesting a role in lipid binding and transport of the E-Syts [9, 24, 25]. A lipid transport function of the E-Syts was further supported by the localization at contacts between intracellular membranes not only of the tricalbin/E-Syts, but also of other known proteins with SMP domains [5], as membrane contacts are sites where lipid transfer between bilayers independent of membrane fusion can occur [26, 27].…”

Single-molecule force spectroscopy of protein-membrane interactions

“…Synaptotagmins (Syts) and extended synaptotagmins (E-Syts) share similar modular structures (Min et al, 2007;Reinisch and De Camilli, 2016;Gustavsson and Han, 2009), including an N-terminal membrane anchor and two to five C-terminal C2 domains, with an additional synaptotagminlike mitochondrial membrane protein (SMP) module in the case of the E-Syts (Alva and Lupas, 2016;Schauder et al, 2014) ( Figure 1B). The C2 domain is one of the most abundant and highly conserved membrane-binding modules, with~200 C2 domains encoded by the human genome (Lemmon, 2008;Corbalan-Garcia and Gó mez-Fernández, 2014).…”

“…Protein-membrane interactions play pivotal roles in numerous biological processes, including membrane protein folding (Yu et al, 2017;Popot and Engelman, 2016;Min et al, 2015), lipid metabolism and transport (Giordano et al, 2013;Reinisch and De Camilli, 2016;Hammond and Balla, 2015;Wong et al, 2017), membrane trafficking (Zhou et al, 2017;Pérez-Lara et al, 2016;Wu et al, 2017;Hurley, 2006;Shen et al, 2012;McMahon and Gallop, 2005), signal transduction (Dong et al, 2017;Aggarwal and Ha, 2016;Lemmon, 2008;Das et al, 2015), and cell motility (Wang and Ha, 2013;Tsujita and Itoh, 2015). Studying these interactions is often difficult, especially when they involve multiple intermediates, multiple ligands, mechanical force, large energy changes, or protein aggregation (Dong et al, 2017;Pérez-Lara et al, 2016;Arauz et al, 2016).…”