Strategies for carbohydrate recognition by the mannose 6-phosphate receptors

Abstract

The two members of the P-type lectin family, the 46 kDa cation-dependent mannose 6-phosphate receptor (CD-MPR) and the 300 kDa cation-independent mannose 6-phosphate receptor (CI-MPR), are ubiquitously expressed throughout the animal kingdom and are distinguished from all other lectins by their ability to recognize phosphorylated mannose residues. The best-characterized function of the MPRs is their ability to direct the delivery of approximately 60 different newly synthesized soluble lysosomal enzymes bearing mannose 6-phosphate (Man-6-P) on their N-linked oligosaccharides to the lysosome. In addition to its intracellular role in lysosome biogenesis, the CI-MPR, but not the CD-MPR, participates in a number of other biological processes by interacting with various molecules at the cell surface. The list of extracellular ligands recognized by this multifunctional receptor has grown to include a diverse spectrum of Man-6-P-containing proteins as well as several non-Man-6-P-containing ligands. Recent structural studies have given us a clearer view of how these two receptors use related, but yet distinct, approaches in the recognition of phosphomannosyl residues.

Granule-Derived Granzyme B Mediates the Vulnerability of Human Neurons to T Cell-Induced Neurotoxicity

“…In addition, in Wang et al (23), the use of recombinant GrB without posttranslational modification and subsequent addition of M6P can also explain these differences. Moreover, although M6PR may interact with several non-M6P-containing ligands, they have much lower affinity for the receptor (47). Furthermore, the constitutively secreted 35-kDa GrB, usually found in the supernatant of activated T cells, lacks the M6P-targeting motif, and this explains its failure to acquire mannose and enter the target cell (24) and to induce significant neuronal death.…”

Extending the Mannose 6-Phosphate Glycoproteome by High Resolution/Accuracy Mass Spectrometry Analysis of Control and Acid Phosphatase 5-Deficient Mice

“…Database locations and creation dates were as follows: ENSEMBL, ftp.ensembl.org/pub/release-68/fasta/rattus_ norvegicus/pep/Rattus_norvegicus.RGSC3. 4 Localization of Candidate Lysosomal Proteins-The subcellular localization of candidate lysosomal proteins was determined using C-terminally tagged fusions with mCherry, a marker that is fluorescent at lysosomal pH and refractory to degradation (16). Constructs were based on pmCherry-N1 (Clontech) and were designed to remove the 11 N-terminal residues of mCherry and all linker sequences between the candidate and the fluorescent tag.…”

Mice Lacking Mannose 6-Phosphate Uncovering Enzyme Activity Have a Milder Phenotype than Mice Deficient forN-Acetylglucosamine-1-Phosphotransferase Activity

“…Furthermore, inactivating mutations in the UCE gene might be very rare events. Finally, it was recently reported that repeat domain 5 (of a total of 15 repeating domains) of the cationindependent mannose 6-phosphate receptor (CI-MPR) is able to bind GlcNAc-P-Man diesters, although this binding was of much lower affinity than the binding of Man-6-P monoesters to domains 1-3 and 9 of the receptor (Chavez et al, 2007; for review, see Dahms et al, 2008). This raises the possibility that, in the absence of UCE activity, acid hydrolases bearing Man-6-P diesters might be able to bind sufficiently to the CI-MPR to allow enough trafficking to lysosomes to prevent the clinical manifestations seen with GlcNAc-1-phosphotransferase deficiency.…”