Faculty Collaboration Database

Structural insights into the mechanism of pH-dependent ligand binding and release by the cation-dependent mannose 6-phosphate receptor. J Biol Chem 2008 Apr 11;283(15):10124-34

Date

02/15/2008

Pubmed ID

18272523

Pubmed Central ID

PMC2442308

DOI

10.1074/jbc.M708994200

Scopus ID

2-s2.0-44349171796 (requires institutional sign-in at Scopus site)   35 Citations

Abstract

The cation-dependent mannose 6-phosphate receptor (CD-MPR) is a key component of the lysosomal enzyme targeting system that binds newly synthesized mannose 6-phosphate (Man-6-P)-containing acid hydrolases and transports them to endosomal compartments. The interaction between the MPRs and its ligands is pH-dependent; the homodimeric CD-MPR binds lysosomal enzymes optimally in the pH environment of the trans Golgi network (pH approximately 6.5) and releases its cargo in acidic endosomal compartments (<pH 5.5) and at the cell surface. In addition, CD-MPR binding affinities are modulated by divalent cations. Our previous crystallographic studies have shown that at pH 6.5, the CD-MPR bound to Man-6-P adopts a significantly different quaternary conformation than the CD-MPR in a ligand-unbound state, a feature unique among known lectin structures. To determine whether different pH conditions elicit conformational changes in the receptor that alters ligand binding affinities, we have obtained additional crystal structures representative of the various environments encountered by the receptor including: 1) the CD-MPR bound at pH 6.5 (i.e. trans Golgi network) to a high affinity ligand (the terminally phosphorylated trisaccharide P-Man(alpha1,2)Man(alpha1,2)Man-O-(CH(2))(8)COOMe), 2) the CD-MPR at pH 4.8 in an unbound state (i.e. endosome), and 3) the CD-MPR at pH 7.4 (i.e. cell surface). A detailed comparison of the available CD-MPR structures reveals the positional invariability of specific binding pocket residues and implicates intermonomer contact(s), as well as the protonation state of Man-6-P, as regulators of pH-dependent carbohydrate binding.

Author List

Olson LJ, Hindsgaul O, 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

Animals
Binding Sites
Biological Transport
Cattle
Endosomes
Hydrogen-Ion Concentration
Lysosomes
Mannosephosphates
Protein Binding
Protein Structure, Quaternary
Receptor, IGF Type 2
trans-Golgi Network