title: Crystal structure of the liganded SCP-2-like domain of human peroxisomal multifunctional enzyme type 2 at 1.75 A resolution.
abstract: beta-Oxidation of amino acyl coenzyme A (acyl-CoA) species in mammalian peroxisomes can occur via either multifunctional enzyme type 1 (MFE-1) or type 2 (MFE-2), both of which catalyze the hydration of trans-2-enoyl-CoA and the dehydrogenation of 3-hydroxyacyl-CoA, but with opposite chiral specificity. MFE-2 has a modular organization of three domains. The function of the C-terminal domain of the mammalian MFE-2, which shows similarity with sterol carrier protein type 2 (SCP-2), is unclear. Here, the structure of the SCP-2-like domain comprising amino acid residues 618-736 of human MFE-2 (d Delta h Delta SCP-2L) was solved at 1.75 A resolution in complex with Triton X-100, an analog of a lipid molecule. This is the first reported structure of an MFE-2 domain. The d Delta h Delta SCP-2L has an alpha/beta-fold consisting of five beta-strands and five alpha-helices; the overall architecture resembles the rabbit and human SCP-2 structures. However, the structure of d Delta h Delta SCP-2L shows a hydrophobic tunnel that traverses the protein, which is occupied by an ordered Triton X-100 molecule. The tunnel is large enough to accommodate molecules such as straight-chain and branched-chain fatty acyl-CoAs and bile acid intermediates. Large empty apolar cavities are observed near the exit of the tunnel and between the helices C and D. In addition, the C-terminal peroxisomal targeting signal is ordered in the structure and solvent-exposed, which is not the case with unliganded rabbit SCP-2, supporting the hypothesis of a ligand-assisted targeting mechanism.
authors.affiliation: Biocenter Oulu and Department of Biochemistry, University of Oulu, FIN-90014, Finland.
authors.forename: A M
authors.initials: AM
authors.lastname: Haapalainen
authors.forename: D M
authors.initials: DM
authors.lastname: van Aalten
authors.forename: G
authors.initials: G
authors.lastname: Meriläinen
authors.forename: J E
authors.initials: JE
authors.lastname: Jalonen
authors.forename: P
authors.initials: P
authors.lastname: Pirilä
authors.forename: R K
authors.initials: RK
authors.lastname: Wierenga
authors.forename: J K
authors.initials: JK
authors.lastname: Hiltunen
authors.forename: T
authors.initials: T
authors.lastname: Glumoff
mesh_terms: D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000737:chemistry* / Q000378:metabolism*; D000595:Amino Acid Sequence; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry*; D018360:Crystallography, X-Ray; D004746:Enoyl-CoA Hydratase / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000378:metabolism*; D017830:Octoxynol / Q000737:chemistry / Q000378:metabolism*; D010940:Plant Proteins; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D055672:Static Electricity; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
chemical_list: D002352:Carrier Proteins; D008024:Ligands; D009097:Multienzyme Complexes; D010940:Plant Proteins; C072087:sterol carrier proteins; D017830:Octoxynol; D015094:3-Hydroxyacyl CoA Dehydrogenases; D004746:Enoyl-CoA Hydratase