Membrane contacts sites (MCSs), regions where two organelles come in close proximity to one another, act as molecular hubs for the exchange of small molecules (e.g. lipids) and signals (e.g. calcium ions). Synaptotagmin-like Mitochondrial lipid-binding Proteins (SMP) domains are exclusively found at MCSs between different organelles such as endoplasmic reticulum (ER)-Mitochondrion, ER-Plasma membrane (PM) and Nucleus-Vacuole junctions. The SMP domain is able to homo- or heterodimerize, harbors lipids in a hydrophobic cavity and mediates lipid transfer between the two adjacent bilayers independently of membrane fusion and fission reactions. SMP proteins are widespread amongst eukaryotic species with a particular enrichment in plants and features suggestive of species-specific functional variations. SMP domain-containing proteins have been classified into four broad groups: C2 domain synaptotagmin-like, PH domain-containing HT-008, PDZK8 and mitochondrial protein families [1,2,3,4,5,6].

The SMP domain consists of 6 β-strands and 3 helices arranged to form a barrel whose interior is lined almost exclusively by hydrophobic residues (see <PDB:4P42>). The resulting elongated barrel-shaped cylindrical structure harbors a lateral opening and a central hydrophobic cavity where phospholipids can bind. It dimerizes in an anti-parallel fashion to form a cylinder traversed by a deep hydrophobic groove [4,5,6]. The SMP domain belongs to the TULIP (for TUbular LIPid-binding) protein superfamily of lipid transfer proteins [7].

Some proteins known to contain a SMP domain are listed below:

• Metazoan PDZD8, a critical endoplasmic reticulum (ER)-mitochondria tethering protein.
• Yeast Mmmm1, Mdm12, and Mdm34, ER-mitochondria encounter structure (ERMES) complex proteins. The ERMES complex functions as a tether between the ER and mitochondria in yeast.
• Mammalian Extended-Synaptotagmins (E-SYTs), ER-resident proteins that act as tethers inking the ER and PM membranes into close apposition. Each E-SYT has an amino-terminal ER-membrane anchor, followed by a short linker region, an SMP domain, and three or more C2 domains (see <PDOC00380>).
• Yeast tricalbins TCB1, TCB2, and TCB3, ER-PM tethers.

The profile we developed covers the entire SMP domain.