Membrane contact sites promote lipid exchange: Most membrane lipids are manufactured in the endoplasmic reticulum (ER). Different organelles and the plasma membrane (PM) have distinct phospholipid compositions. Chung et al. , working in mammalian cells, and Moser von Filseck et al. , working in yeast, both describe how a family of proteins is important in maintaining the balance of lipids within the cell. These special proteins accumulate at and tether contact sites between the ER and the PM and promote the exchange of specific phospholipids, which helps to maintain the PM's distinct identity. Science , this issue pp. 428 and 432

Several proteins localized at membrane contact sites contain an SMP domain, which has been proposed to act as a lipid-binding module; here, the crystal structure of a fragment of the extended synaptotagmin 2 protein, including its SMP, is presented, and indicates that this protein may have a direct role in lipid transport. Growing evidence suggests that close appositions between the endoplasmic reticulum (ER) and other membranes, including appositions with the plasma membrane (PM), mediate exchange of lipids between these bilayers. The mechanisms of such exchange, which allows lipid transfer independently of vesicular transport, remain poorly understood. The presence of a synaptotagmin-like mitochondrial-lipid-binding protein (SMP) domain, a proposed lipid-binding module, in several proteins localized at membrane contact sites has raised the possibility that such domains may be implicated in lipid transport1,2. SMP-containing proteins include components of the ERMES complex, an ER–mitochondrial tether3, and the extended synaptotagmins (known as tricalbins in yeast), which are ER–PM tethers4,5,6. Here we present at 2.44 Å resolution the crystal structure of a fragment of human extended synaptotagmin 2 (E-SYT2), including an SMP domain and two adjacent C2 domains. The SMP domain has a β-barrel structure like protein modules in the tubular-lipid-binding (TULIP) superfamily. It dimerizes to form an approximately 90-Å-long cylinder traversed by a channel lined entirely with hydrophobic residues, with the two C2A–C2B fragments forming arched structures flexibly linked to the SMP domain. Importantly, structural analysis complemented by mass spectrometry revealed the presence of glycerophospholipids in the E-SYT2 SMP channel, indicating a direct role for E-SYTs in lipid transport. These findings provide strong evidence for a role of SMP-domain-containing proteins in the control of lipid transfer at membrane contact sites and have broad implications beyond the field of ER-to-PM appositions.

Bo Burla, Makoto Arita, Masanori Arita, Anne K. Bendt, Amaury Cazenave-Gassiot, Edward A. Dennis, Kim Ekroos, Xianlin Han, Kazutaka Ikeda, Gerhard Liebisch, Michelle K. Lin, Tze Ping Loh, Peter J. Meikle, Matej Orešič, Oswald Quehenberger, Andrej Shevchenko, Federico Torta, Michael J. O. Wakelam, Craig E. Wheelock, Markus R. Wenk

Metabolite channeling by a dynamic metabolon: The specialized metabolite dhurrin breaks down into cyanide when plant cell walls have been chewed, deterring insect pests. Laursen et al. found that the enzymes that synthesize dhurrin in sorghum assemble as a metabolon in lipid membranes (see the Perspective by Dsatmaichi and Facchini). The dynamic nature of metabolon assembly and disassembly provides dhurrin on an as-needed basis. Membrane-anchored cytochrome P450s cooperated with a soluble glucosyltransferase to channel intermediates toward efficient dhurrin production. Science , this issue p. 890 ; see also p. 829

Understanding insulin release: Insulin release takes place in two phases: a first rapid burst followed by a series of small exocytic bursts that coincide with pulsatile spikes in cytosolic Ca ²⁺ levels. The second phase is impaired in patients with type II diabetes, underscoring the importance of understanding its molecular basis. Lees et al. report a mechanism through which TMEM24, a lipid transport protein that concentrates at endoplasmic reticulum–plasma membrane contact sites, regulates the pulsatility of cytosolic Ca ²⁺ and phosphoinositide signaling. This process in turn regulates pulsatile insulin secretion during the slow insulin release phase. Science , this issue p. eaah6171