Faculty Collaboration Database

Twists and turns of the cation-dependent mannose 6-phosphate receptor. Ligand-bound versus ligand-free receptor. J Biol Chem 2002 Mar 22;277(12):10156-61

Date

01/12/2002

Pubmed ID

11786557

DOI

10.1074/jbc.M112230200

Scopus ID

2-s2.0-0037155883 (requires institutional sign-in at Scopus site)   43 Citations

Abstract

Mannose 6-phosphate receptors (MPRs) participate in the biogenesis of lysosomes in higher eukaryotes by transporting soluble acid hydrolases from the trans-Golgi network to late endosomal compartments. The receptors release their ligands into the acidic environment of the late endosome and then return to the trans-Golgi network to repeat the process. However, the mechanism that facilitates ligand binding and dissociation upon changes in pH is not known. We report the crystal structure of the extracytoplasmic domain of the homodimeric cation-dependent MPR in a ligand-free form at pH 6.5. A comparison of the ligand-bound and ligand-free structures reveals a significant change in quaternary structure as well as a reorganization of the binding pocket, with the most prominent change being the relocation of a loop (residues Glu(134)-Cys(141)). The movements involved in the bound-to-free transition of the cation-dependent MPR are reminiscent of those of the oxy-to-deoxy hemoglobin transition. These results allow us to propose a mechanism by which the receptor regulates its ligand binding upon changes in pH; the pK(a) of Glu(133) appears to be responsible for ligand release in the acidic environment of the late endosomal compartment, and the pK(a) values of the sugar phosphate and His(105) are accountable for its inability to bind ligand at the cell surface where the pH is about 7.4.

Author List

Olson LJ, Zhang J, Dahms NM, Kim JJ

Authors

Nancy M. Dahms PhD Professor in the Biochemistry department at Medical College of Wisconsin
Jung Ja P. Kim PhD Professor in the Biochemistry department at Medical College of Wisconsin
Linda J. Olson PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Binding Sites
Circular Dichroism
Cysteine
Cytoplasm
Dimerization
Endosomes
Glutamic Acid
Histidine
Hydrogen-Ion Concentration
Ligands
Models, Molecular
Molecular Sequence Data
Phosphates
Protein Binding
Protein Conformation
Protein Folding
Protein Structure, Secondary
Protein Structure, Tertiary
Receptor, IGF Type 2
Sequence Homology, Amino Acid