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Mannose 6-phosphate receptors: new twists in the tale

Key Points

  • ;Mannose 6-phosphate (M6P) receptors (the CD-MPR and CI-MPR) are type-I integral membrane glycoproteins that constitute the family of p-type lectins. They bind to M6P-containing lysosomal acid hydrolases and transport them from the Golgi to the endosomal–lysosomal system.

  • X-ray crystallographic studies have provided an understanding of the molecular mechanisms that govern carbohydrate recognition by the MPRs, and IGF-II recognition by the CI-MPR. A relatively deep carbohydrate-recognition domain accounts for the numerous interactions between the CD-MPR and its carbohydrate ligands. The liganded versus unliganded molecule shows a considerable conformational change that enables ligand binding by the receptor.

  • The MPRs have a complex intracellular trafficking itinerary that includes cycling between the Golgi and the endosomes, and delivering acid hydrolases to the endosomal compartments. The anterograde trafficking of the MPRs is through GGA-assisted packaging into AP1-containing clathrin-coated carriers, whereas the retrieval from the endosomal system occurs through a combination of the PACS-1/AP1 and TIP47/Rab9 pathways. MPRs that reach the cell surface are internalized rapidly by AP2.

  • The CI-MPR has further functions at the cell surface that include internalization of IGF-II for degradation in lysosomes and activation of latent transforming growth factor (TGF)-β1.

  • Loss of heterozygosity at the CI-MPR locus has been reported in several human cancers. In several instances, the M6P- and IGF-II-binding domains of the remaining allele have been found to have mutations. Where examined, most of the mutations disrupted M6P- and/or IGF-II-binding properties. This supports the proposal that loss of normal CI-MPR function contributes to carcinogenesis, making it a candidate tumour-suppressor gene.

Abstract

The two mannose 6-phosphate (M6P) receptors were identified because of their ability to bind M6P-containing soluble acid hydrolases in the Golgi and transport them to the endosomal–lysosomal system. During the past decade, we have started to understand the structural features of these receptors that allow them to do this job, and how the receptors themselves are sorted as they pass through various membrane-bound compartments. But trafficking of acid hydrolases is only part of the story. Evidence is emerging that one of the receptors can regulate cell growth and motility, and that it functions as a tumour suppressor.

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Figure 1: The MPRs are type-I transmembrane glycoproteins.
Figure 2: The crystal structure of the extracytoplasmic region of the bovine CD-MPR.
Figure 3: Comparison of the CI-MPR domain 11 and CD-MPR structures.
Figure 4: A schematic representation of the subcellular localization and trafficking itinerary of the MPRs.
Figure 5: Sorting signals on MPR tails.
Figure 6: The structure of the GGA3 VHS domain bound to its ligand.
Figure 7: Architecture of the trans-Golgi network and its relevance to MPR trafficking.

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Acknowledgements

We thank C. Byrd, D. Tollefsen, K. Howell, R. Kornfeld and members of the Kornfeld laboratory for their critical reading of the manuscript and helpful suggestions.

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DATABASES

Swiss-Prot

CD-MPR

CD26

CI-MPR

EEA1

GGA1

GGA2

GGA3

granzyme B

IGF-binding protein 5

IGF-I

IGF-II

plasminogen

rabaptin5

syntaxin 6

syntaxin 13

TGF-β1

TIP47

uPAR

VAMP-4

Glossary

ADAPTORS

Heterotetrameric protein complexes that connect molecules on membranes and structural coat proteins, for example clathrin. AP1 mediates cargo transport between the trans-Golgi network (TGN) and endosomes through the generation of clathrin-coated carriers.

CLATHRIN-COATED BUDS AND VESICLES

These are membrane evaginations that have assembled clathrin on their surface. The forming vesicles bud off and function as carriers for sorted proteins.

GGA

A multidomain, cytosolic protein with an amino-terminal VHS domain that binds cargo, followed by a coiled-coil GAT domain that mediates membrane recruitment through ARF; a variable hinge segment that contains clathrin- and AP1-binding regions; and a carboxy-terminal ear domain, which recruits accessory proteins and has homology to the γ-appendage. These molecules have recently been implicated in the sorting of MPRs at the TGN.

VHS DOMAIN

An approximately 150-residue domain whose name is derived from its presence in VPS-27, Hrs and STAM. It is found at the amino termini of proteins that are associated with endocytosis and/or vesicular trafficking.

CK-2 SITE

(casein kinase 2). A phosphorylation site that is characterized by the presence of phosphoacceptor residues (S/T) that are flanked by clusters of negatively charged amino acids, the residue at position n+3 being one of the following: an aspartate, glutamate, phosphoserine or phosphothreonine. The minimum concensus sequence is S/T XX D/E/pS/pT.

ELECTRON TOMOGRAPHY

A general method for the three-dimensional reconstruction of single, transparent objects from a series of projection images (that is, from a tilt series) that are recorded with a transmission electron microscope.

HSC70

(heat shock cognate protein of 70kDa). Proteins of this chaperone family are involved in a range of cellular processes, such as protein folding, translocation across membranes and the assembly or disassembly of protein complexes.

AUXILIN

A neuronal protein that contains a clathrin-binding site and a carboxy-terminal J-domain that interacts with and stimulates the dormant ATPase of the chaperone Hsc70.

KIF13A

(kinesin family 13A). A novel plus-end-directed microtubule-dependent motor protein that associates with mannose 6-phosphate receptor (MPR)-containing carriers through the β1-subunit of AP1.

RAB PROTEINS

Monomeric small GTPases which, along with their effectors, mediate the first specific event during membrane fusion; that is, tethering of an incoming vesicle to the correct target organelle.

SNARES

(soluble N-ethyl-maleimide-sensitive (NSF) attachment protein receptors). Proteins that are implicated in mediating most intracellular membrane-fusion events by interacting with each other to generate the driving force needed to fuse lipid bilayers.

TIP47

(tail-interacting protein, 47 kDa). A novel hydrophilic, cytosolic protein of 47 kDa that binds directly to cytoplasmic tails of both the cation-independent and cation-dependent MPRs and is involved in sorting at the endosomes.

PACS-1

(phosphofurin acidic cluster-sorting protein). A cytosolic linker molecule that connects proteins such as furin, HIV virus type-1 (HIV-1) Nef and the CI-MPR, through their acidic-cluster sorting motifs, to adaptors (AP1 and AP3, but not AP2).

SERTOLI CELL

A cell that is located in the male gonads and provides nourishment to sperm.

LOSS OF HETEROZYGOSITY

A loss of either the maternal or paternal allele of a gene. This is often a molecular marker of a tumour-suppressor gene locus.

MICROSATELLITE INSTABILITY

(MSI). Alterations of the length of simple repetitive genomic sequences. In tumours it is an indication that there have probably been mutations in genes encoding proteins that are involved in DNA repair.

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Ghosh, P., Dahms, N. & Kornfeld, S. Mannose 6-phosphate receptors: new twists in the tale. Nat Rev Mol Cell Biol 4, 202–213 (2003). https://doi.org/10.1038/nrm1050

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