In silico analysis of coevolution among ERMES proteins, Pex11, and Lam6.

In eukaryotic cells, communication and dynamic interactions among different organelles are important for maintaining cellular homeostasis. The endoplasmic reticulum (ER) mitochondria encounter structure (ERMES) complex establishes membrane contact sites between ER and mitochondria and is essential for phospholipid transport, protein import, and mitochondrial dynamics and inheritance. In this work, in silico analyses were used to probe the intramolecular interactions in ERMES proteins and the interactions that support the ERMES complex. Based on mutual information (MI), sites of intramolecular coevolution are predicted in the core proteins Mmm1, Mdm10, Mdm12, Mdm34, the peroxisomal protein Pex11, and cytoplasmic Lam6; these sites are linked to structural features of the proteins. Intermolecular coevolution is predicted among the synaptotagmin-like mitochondrial lipid-binding protein (SMP) domains of Mmm1, Mdm12, and Mdm34. Segments of Pex11 and Lam6 also share MI with the SMP domains of Mmm1 and Mdm12 and with the N terminus of Mdm34, implicating Mdm34 as part of a hub for interactions between ERMES and other complexes. In contrast, evidence of limited intermolecular coevolution involving the outer membrane protein Mdm10 was detected only with Mmm1 and Pex11. The results support models for the organization of these interacting proteins and suggest roles for Pex11 and Lam6 in regulating complex formation.