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Mannose 6-Phosphate Receptors: New Twists in the Tale

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Mannose 6-Phosphate Receptors: New Twists in the Tale REVIEWS MANNOSE 6-PHOSPHATE RECEPTORS: NEW TWISTS IN THE TALE Pradipta Ghosh*, Nancy M. Dahms‡ and Stuart Kornfeld* 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. The two mannose 6-phosphate (M6P) receptors CI-MPR acts as a tumour suppressor, probably through (MPRs) — the ~46-kDa cation-dependent MPR these growth-inhibitory functions. Moreover, insights (CD-MPR) and the ~300-kDa cation-independent have been gained into the molecular mechanisms that MPR/insulin-like growth factor-II (IGF-II) receptor govern carbohydrate and IGF-II recognition by the (CI-MPR) — are the sole members of the family of MPRs, and the cellular components that mediate the p-type lectins1. The CI-MPR is a multifunctional recep- transport of the receptors through numerous intracel- tor that carries out several tasks that are essential for lular compartments. This review focuses on these recent normal cellular function. One such task, which is shared findings. Other reviews summarize earlier studies of the with the CD-MPR, is the delivery of newly synthesized MPRs2–4 and the crystal structure of the CD-MPR1. acid hydrolases from the trans-Golgi network (TGN) to endosomes for their subsequent transfer to lysosomes. The structures of the MPRs This process involves binding of the hydrolases, through The two MPRs are type-1 integral membrane glyco- their M6P-recognition moieties, to the receptors, pack- proteins (FIG. 1). The extracytoplasmic region of the aging of the ligand–receptor complexes into carriers CI-MPR has a repetitive structure that consists of 15 *Department of Internal that transport their cargo to target endosomes and recy- contiguous repeats of approximately 147 amino acids Medicine, Washington University School of cling of the receptors back to the TGN. each. The repeating segments share sequence identity Medicine, In addition to this shared function, the CI-MPR has (14–38%) and cysteine distribution, which gives rise to 660 South Euclid Avenue, been implicated in several other physiological processes. the possibility that they have similar disulphide-bond- St Louis, Missouri 63110, It binds IGF-II at the cell surface and internalizes this ing and tertiary structures5. The 159-residue extracyto- USA. growth factor for degradation in lysosomes. This pre- plasmic domain of the CD-MPR is similar to the ‡Department of Biochemistry, Medical vents the accumulation of excessive levels of IGF-II, repeating units of the CI-MPR. College of Wisconsin, which are detrimental, especially during embryonic The CI-MPR extracytoplasmic domain contains Milwaukee, development. It facilitates the activation of the latent two distinct M6P-binding sites (repeating segments 3 Wisconsin 53226, USA. precursor of transforming growth factor-β1 (TGF-β1) and 9) and a single IGF-II-binding site (segment 11)6–9, Correspondence to S.K. e-mail: and it mediates the uptake of granzyme B, which is a whereas the CD-MPR contains a single M6P-binding [email protected] serine protease involved in cytotoxic-T-cell-induced site and does not bind IGF-II. The cytoplasmic tails of doi:10.1038/nrm1050 apoptosis. There is also evidence indicating that the both receptors contain numerous sorting signals, some 202 | MARCH 2003 | VOLUME 4 www.nature.com/reviews/molcellbio © 2003 Nature PublishingGroup REVIEWS uPAR terminal M6P residue and the penultimate sugar ring of X-M6P M6P-containing protein 1 1 uPAR bound pentamannosyl phosphate are mostly buried in Plg 17 Plg 2 2 the receptor . This deep binding pocket facilitates the Extracytoplasmic domain 3 M6P- 3 formation of numerous interactions between the X -M6P CD-MPR and its carbohydrate ligands. The structure of Fibronectin type-II like insert 5 5 the ligand-free receptor differs considerably from the 6 6 (FIG. 2a,b) Transmembrane domain liganded receptor molecule . This indicates that 7 7 the ‘free-to-bound’ transition requires the receptor Cytoplasmic tail 8 8 monomer to undergo significant scissoring and twisting Palmitoylation 9 M6P- 9 movements, such that the ‘closed’ ligand-free conforma- 18 P Phosphorylation X -M6P tion is ‘opened’ up to allow ligand binding . 11 11 A structure-based sequence alignment between the 12 12 IGF-II CD-MPR and domains 3 and 9 of the CI-MPR provides IGF-II X-M6P 13 13 evidence that both receptors use a similar carbohydrate- 14 14 16 M6P-X recognition mechanism . This was confirmed by site- 15 15 directed mutagenesis studies, which showed that the two binding sites of the CI-MPR use the same essential amino acids for ligand binding6 (FIG. 2c).However,the P P P P M6P-binding domains of the CI-MPR lack a residue that is analogous to aspartic acid 103, which coordinates P P divalent cations, explaining why only the CD-MPR CD-MPR CI-MPR shows enhanced ligand binding in the presence of diva- Figure 1 | The MPRs are type-I transmembrane glycoproteins. The cation-dependent lent cations. mannose 6-phosphate (M6P) receptor (CD-MPR) is present predominantly as a stable The overall structure of the IGF-II binding domain homodimer in membranes and has a single M6P-binding site per polypeptide. The 11 of the CI-MPR is similar to that of the CD-MPR19 cation-independent (CI)-MPR seems to be a dimer in the membrane, although it tends to act as a (FIG. 3a,b). However, the molecule contains a surface monomer in detergent solutions. Various post-translational modifications of the MPRs occur, hydrophobic patch that equates spatially to the including palmitoylation and phosphorylation. uPAR, urokinase (plasminogen activator) receptor; hydrophilic M6P-binding pocket on the CD-MPR, IGF-II, insulin-like growth factor; Plg, plasminogen. explaining the lack of carbohydrate binding by CI- MPR domain 11 (FIG. 3c,d). This hydrophobic patch is probably involved in IGF-II binding as it contains of which are modified by phosphorylation10,11 or palmi- isoleucine 1572, which is required for this interaction9. toylation12. The CD-MPR is present primarily as a non- As the residues on IGF-II that are essential for binding covalent homodimer in the membrane1. The CI-MPR to the CI-MPR form a hydrophobic patch on the sur- also seems to be a dimer in the membrane, although it face, it is probable that the interaction of IGF-II with behaves as a monomer in detergent solutions under the CI-MPR is predominantly hydrophobic. This is most circumstances13–15. Receptor dimerization allows similar to the interaction of the homologous IGF-I with for high-affinity binding of ligands that are multivalent IGF-binding protein 5 (REF. 20). for M6P residues14–15. The short linker length between the CI-MPR repeat- Important insights into the function of the MPRs ing segments (5–12 residues) places considerable con- have come from X-ray crystallographic studies of the straints on possible arrangements of the domains in the three-dimensional structure of the extracytoplasmic intact receptor, and Brown et al.19 have proposed a region of the CD-MPR, both in the unliganded state model in which even-numbered domains face one and complexed to either M6P or pentamannosyl phos- direction and odd-numbered domains face the opposite phate16–18. In both liganded and unliganded forms, the direction (FIG. 1). In this model, the putative IGF-II molecule crystallized as a homodimer with approxi- binding face of domain 11 is adjacent to the region of mately 20% of the entire surface area of each monomer domain 13 that contains a fibronectin type II-like having contact with another through predominantly insert, which contributes to the enhancement of IGF-II hydrophobic interactions (FIG. 2a). Each monomer con- binding by domain 13 (REFS 21,22). As all of the known tains a single α-helix near its amino terminus followed functional domains of the CI-MPR have odd num- by nine primarily anti-parallel β-strands that form two bers, it is possible that one side of the molecule is β-sheets, which are positioned orthogonally to each involved in ligand interactions, whereas the opposite other. Extensive hydrophobic interactions are formed surface has another role, such as mediating dimeriza- between the two β-sheets, which results in each tion. This would be similar to what has been found monomer forming a flattened β-barrel structure. with the CD-MPR (FIG. 2). The six cysteine residues form three intramolecular disulphide bonds that are essential for the ligand-binding MPR trafficking — the itinerary conformation of the receptor to be generated. The MPRs are found in the TGN, early (sorting) endo- structures of the liganded molecules show that the car- somes, recycling endosomes, late endosomes and the bohydrate-recognition domain (CRD) of the CD- plasma membrane, but they are conspicuously MPR lies relatively deep inside the protein, so that the absent from lysosomes (FIG. 4). The receptors cycle NATURE REVIEWS | MOLECULAR CELL BIOLOGY VOLUME 4 | MARCH 2003 | 203 © 2003 Nature PublishingGroup REVIEWS ab c C C N104 D103 H105 4 D S430 /S431 B D N 4 H1329 3 Mn A 5 3 B R135 N 2 H O Y45 5 E133 2 Y368 6 H1 2 A 9 1 6 E460 Y1264 H 7 7 9 8 M6P 1 E1354 R111 C R435 Q66 R1334 Q392 Y143 Q1292 Y465 Y1360 ADAPTORS Heterotetrameric protein Figure 2 | The crystal structure of the extracytoplasmic region of the bovine CD-MPR.
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