Medical College of Wisconsin
CTSICores SearchResearch InformaticsREDCap

Allosteric regulation of lysosomal enzyme recognition by the cation-independent mannose 6-phosphate receptor. Commun Biol 2020 Sep 09;3(1):498

Date

09/11/2020

Pubmed ID

32908216

Pubmed Central ID

PMC7481795

DOI

10.1038/s42003-020-01211-w

Scopus ID

2-s2.0-85090384984 (requires institutional sign-in at Scopus site)   16 Citations

Abstract

The cation-independent mannose 6-phosphate receptor (CI-MPR, IGF2 receptor or CD222), is a multifunctional glycoprotein required for normal development. Through the receptor's ability to bind unrelated extracellular and intracellular ligands, it participates in numerous functions including protein trafficking, lysosomal biogenesis, and regulation of cell growth. Clinically, endogenous CI-MPR delivers infused recombinant enzymes to lysosomes in the treatment of lysosomal storage diseases. Although four of the 15 domains comprising CI-MPR's extracellular region bind phosphorylated glycans on lysosomal enzymes, knowledge of how CI-MPR interacts with ~60 different lysosomal enzymes is limited. Here, we show by electron microscopy and hydroxyl radical protein footprinting that the N-terminal region of CI-MPR undergoes dynamic conformational changes as a consequence of ligand binding and different pH conditions. These data, coupled with X-ray crystallography, surface plasmon resonance and molecular modeling, allow us to propose a model explaining how high-affinity carbohydrate binding is achieved through allosteric domain cooperativity.

Author List

Olson LJ, Misra SK, Ishihara M, Battaile KP, Grant OC, Sood A, Woods RJ, Kim JP, Tiemeyer M, Ren G, Sharp JS, Dahms NM

Authors

Nancy M. Dahms PhD Professor in the Biochemistry department at Medical College of Wisconsin
Linda J. Olson PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




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

Allosteric Regulation
Binding Sites
Cations
Crystallography, X-Ray
Humans
Hydroxyl Radical
Ligands
Lysosomal Storage Diseases
Lysosomes
Mannose
Microscopy, Electron
Protein Conformation
Protein Footprinting
Receptor, IGF Type 2
Surface Plasmon Resonance