Abstract
Members of the mitochondrial carrier family [solute carrier family 25 (SLC25)] transport nucleotides, amino acids, carboxylic acids, fatty acids, inorganic ions, and vitamins across the mitochondrial inner membrane. They are important for many cellular processes, such as oxidative phosphorylation of lipids and sugars, amino acid metabolism, macromolecular synthesis, ion homeostasis, cellular regulation, and differentiation. Here, we describe the functional elements of the transport mechanism of mitochondrial carriers, consisting of one central substrate-binding site and two gates with salt-bridge networks on either side of the carrier. Binding of the substrate during import causes three gate elements to rotate inward, forming the cytoplasmic network and closing access to the substrate-binding site from the intermembrane space. Simultaneously, three core elements rock outward, disrupting the matrix network and opening the substrate-binding site to the matrix side of the membrane. During export, substrate binding triggers conformational changes involving the same elements but operating in reverse. Expected final online publication date for the Annual Review of Biochemistry, Volume 90 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Highlights
Introduction to the Theme on MembraneChannels Gunnar von Heijne pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp 503The Form and Function of PIEZO2 Marcin Szczot, Alec R
Most structural information for the SLC25 family has come from crystallographic studies of the mitochondrial ADP/ATP carrier due to its high natural abundance and to the availability of specific inhibitors that lock the carrier in two different conformational states [17, 18]
Projection maps revealed that the carrier is monomeric and has a threefold pseudosymmetric structure, consistent with the three homologous repeats, and a central substrate translocation pathway. This was followed by the atomic structure of the bovine ADP/ATP carrier trapped in the c-state by CATR [Protein Data Bank identifiers (PDB IDs) 1OKC and 2C3E] [43, 44]
Summary
Most structural information for the SLC25 family has come from crystallographic studies of the mitochondrial ADP/ATP carrier due to its high natural abundance and to the availability of specific inhibitors that lock the carrier in two different conformational states [17, 18]. Projection maps revealed that the carrier is monomeric and has a threefold pseudosymmetric structure, consistent with the three homologous repeats, and a central substrate translocation pathway. This was followed by the atomic structure of the bovine ADP/ATP carrier trapped in the c-state by CATR [Protein Data Bank identifiers (PDB IDs) 1OKC and 2C3E] [43, 44]. The first structure has been solved for an SLC25 family member in the m-state—the ADP/ATP carrier from the thermotolerant fungus Thermothelomyces thermophila (TtAac) inhibited by BKA [47]. A mutation of the cytoplasmic salt-bridge network (see Section 2.3) and a conformationally specific nanobody [48] raised against the BKA-inhibited protein stabilized the protein sufficiently to produce diffracting crystals for the structure determination
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