title: Structural basis for universal corrinoid recognition by the cobalamin transport protein haptocorrin.
abstract: Cobalamin (Cbl; vitamin B12) is an essential micronutrient synthesized only by bacteria. Mammals have developed a sophisticated uptake system to capture the vitamin from the diet. Cbl transport is mediated by three transport proteins: transcobalamin, intrinsic factor, and haptocorrin (HC). All three proteins have a similar overall structure but a different selectivity for corrinoids. Here, we present the crystal structures of human HC in complex with cyanocobalamin and cobinamide at 2.35 and 3.0 Å resolution, respectively. The structures reveal that many of the interactions with the corrin ring are conserved among the human Cbl transporters. However, the non-conserved residues Asn-120, Arg-357, and Asn-373 form distinct interactions allowing for stabilization of corrinoids other than Cbl. A central binding motif forms interactions with the e- and f-side chains of the corrin ring and is conserved in corrinoid-binding proteins of other species. In addition, the α- and β-domains of HC form several unique interdomain contacts and have a higher shape complementarity than those of intrinsic factor and transcobalamin. The stabilization of ligands by all of these interactions is reflected in higher melting temperatures of the protein-ligand complexes. Our structural analysis offers fundamental insights into the unique binding behavior of HC and completes the picture of Cbl interaction with its three transport proteins.
authors.affiliation: From the Center for Radiopharmaceutical Sciences and.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Furger
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, CH-5232 Villigen PSI and.
authors.forename: Dominik C
authors.initials: DC
authors.lastname: Frei
authors.affiliation: From the Center for Radiopharmaceutical Sciences and; the Institute of Pharmaceutical Sciences, Eidgenössische Technische Hochschule (ETH) Zürich, CH-8093 Zürich, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Schibli
authors.affiliation: From the Center for Radiopharmaceutical Sciences and. Electronic address: eliane.fischer@psi.ch.
authors.forename: Eliane
authors.initials: E
authors.lastname: Fischer
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, CH-5232 Villigen PSI and. Electronic address: andrea.prota@psi.ch.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Prota
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D003038:Cobamides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014155:Transcobalamins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D003038:Cobamides; D014155:Transcobalamins
keywords: Biosynthesis; Cobalamin; Cobinamide; Cofactors; Corrinoids; Crystal Structure; Haptocorrin; Metabolism; Nutrition; Vitamins