Description
Crystal structures of Mmm1 and Mdm12-Mmm1 reveal mechanistic insight into phospholipid trafficking at ER-mitochondria contact sites
Hanbin Jeong1,2, Jumi Park1,2, Hakbong Lee1,2, Youngsoo Jun2,3, Changwook Lee1,2,4,*
1Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Republic of Korea; 2Cell Logistics Research Center, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea; 3School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea; 4Center for Genome Integrity, Institute for Basic Science, Ulsan 44919, Republic of Korea
*Corresponding Author
The endoplasmic reticulum (ER)-mitochondria encounter structure (ERMES) comprises mitochondrial distribution and morphology 12 (Mdm12), maintenance of mitochondrial morphology 1 (Mmm1), Mdm34, and Mdm10 and mediates physical membrane contact sites and nonvesicular lipid trafficking between the ER and mitochondria in yeast. Herein, we report two crystal structures of the synaptotagmin-like mitochondrial lipid-binding protein (SMP) domain of Mmm1 and the Mdm12-Mmm1 complex at 2.8 Å and 3.8 Å resolution, respectively. Mmm1 adopts a dimeric SMP structure augmented with two extra structural elements at the N and C termini that are involved in tight self-association and phospholipid coordination. Mmm1 binds two phospholipids inside the hydrophobic cavity, and the phosphate ion of the distal phospholipid is specifically recognized through extensive H-bonds. A positively charged concave surface on the SMP domain not only mediates ER membrane docking but also results in preferential binding to glycerophospholipids such as phosphatidylcholine (PC), phosphatidic acid (PA), phosphatidylglycerol (PG), and phosphatidylserine (PS), some of which are substrates for lipid-modifying enzymes in mitochondria. The Mdm12-Mmm1 structure reveals two Mdm12s binding to the SMP domains of the Mmm1 dimer in a pairwise head-to-tail manner. Direct association of Mmm1 and Mdm12 generates a 210-Å-long continuous hydrophobic tunnel that facilitates phospholipid transport. The Mdm12-Mmm1 complex binds all glycerophospholipids except for phosphatidylethanolamine (PE) in vitro.
References
Jeong H, Park J, Jun Y, Lee C. Crystal structures of Mmm1 and Mdm12-Mmm1 reveal mechanistic insight into phospholipid trafficking at ER-mitochondria contact sites. Proceedings of the National Academy of Sciences. 2017 Oct 25:201715592.
Jeong H, Park J, Lee C. Crystal structure of Mdm12 reveals the architecture and dynamic organization of the ERMES complex. EMBO reports. 2016 Nov 7:e201642706.