Structural insight into the TRIAP1/PRELI-like domain family of mitochondrial phospholipid transfer complexes

The composition of the mitochondrial membrane is important for its architecture and proper function. Mitochondria depend on a tightly regulated supply of phospholipid via intra-mitochondrial synthesis and by direct import from the endoplasmic reticulum. The Ups1/PRELI-like family together with its mitochondrial chaperones (TRIAP1/Mdm35) represent a unique heterodimeric lipid transfer system that is evolutionary conserved from yeast to man. Work presented here provides new atomic resolution insight into the function of a human member of this system. Crystal structures of free TRIAP1 and the TRIAP1-SLMO1 complex reveal how the PRELI domain is chaperoned during import into the intermembrane mitochondrial space. The structural resemblance of PRELI-like domain of SLMO1 with that of mammalian phoshatidylinositol transfer proteins (PITPs) suggest that they share similar lipid transfer mechanisms, in which access to a buried phospholipid-binding cavity is regulated by conformationally adaptable loops. Synopsis The structures of TRIAP1 and its complex with SLMO1 reveal how the PRELI domain is chaperoned during mitochondrial import. Access to an internal phospholipid binding cavity is likely regulated by conformationally adaptable loops. Structures of TRIAP1 and the TRIAP1-SLMO1 complex were solved by X-ray crystallography. The PRELI-like domain of SLMO1 resembles that of mammalian phoshatidylinositol transfer proteins (PITPs). Mutagenesis experiments highlight the roles of an internal hydrophilic cavity and lipid exchange loops in phospholipid extraction. The structures of TRIAP1 and its complex with SLMO1 reveal how the PRELI domain is chaperoned during mitochondrial import. Access to an internal phospholipid binding cavity is likely regulated by conformationally adaptable loops.