The endoplasmic reticulum–mitochondria encounter structure (ERMES) is a protein complex that plays a tethering role in physically connecting ER and mitochondria membranes. The ERMES complex is composed of Mdm12, Mmm1, and Mdm34, which have a SMP domain in common, and Mdm10. Here, we report the crystal structure of S. cerevisiae Mdm12. The Mdm12 forms a dimeric SMP structure through domain swapping of the β1‐strand comprising residues 1–7. Biochemical experiments reveal a phospholipid‐binding site located along a hydrophobic channel of the Mdm12 structure and that Mdm12 might have a binding preference for glycerophospholipids harboring a positively charged head group. Strikingly, both full‐length Mdm12 and Mdm12 truncated to exclude the disordered region (residues 74–114) display the same organization in the asymmetric unit, although they crystallize as a tetramer and hexamer, respectively. Taken together, these studies provide a novel understanding of the overall organization of SMP domains in the ERMES complex, indicating that Mdm12 interacts with Mdm34 through head‐to‐head contact, and with Mmm1 through tail‐to‐tail contact of SMP domains.
The crystal structure of Mdm12, a cytosolic component of the ER–mitochondria encounter structure (ERMES) complex, reveals the structural basis for phospholipid binding and selectivity of Mdm12, and the organization of SMP domains in the ERMES complex.
The crystal structure of Mdm12 reveals a highly conserved β1‐strand that is critical for oligomerization.
The SMP domain of Mdm12 selectively binds phospholipids with a positively charged head group via a negatively charged surface platform.
Biochemical analysis suggests that Mdm12 provides two distinct contact sites to connect Mmm1 and Mdm34.
- Received May 11, 2016.
- Revision received September 23, 2016.
- Accepted September 30, 2016.
- © 2016 The Authors