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• W2021989115 abstract "Mannose 6-phosphate receptors (MPRs) play an important role in the targeting of newly synthesized soluble acid hydrolases to the lysosome in higher eukaryotic cells. These acid hydrolases carry mannose 6-phosphate recognition markers on theirN-linked oligosaccharides that are recognized by two distinct MPRs: the cation-dependent mannose 6-phosphate receptor and the insulin-like growth factor II/cation-independent mannose 6-phosphate receptor. Although much has been learned about the MPRs, it is unclear how these receptors interact with the highly diverse population of lysosomal enzymes. It is known that the terminal mannose 6-phosphate is essential for receptor binding. However, the results from several studies using synthetic oligosaccharides indicate that the binding site encompasses at least two sugars of the oligosaccharide. We now report the structure of the soluble extracytoplasmic domain of a glycosylation-deficient form of the bovine cation-dependent mannose 6-phosphate receptor complexed to pentamannosyl phosphate. This construct consists of the amino-terminal 154 amino acids (excluding the signal sequence) with glutamine substituted for asparagine at positions 31, 57, 68, and 87. The binding site of the receptor encompasses the phosphate group plus three of the five mannose rings of pentamannosyl phosphate. Receptor specificity for mannose arises from protein contacts with the 2-hydroxyl on the terminal mannose ring adjacent to the phosphate group. Glycosidic linkage preference originates from the minimization of unfavorable interactions between the ligand and receptor. Mannose 6-phosphate receptors (MPRs) play an important role in the targeting of newly synthesized soluble acid hydrolases to the lysosome in higher eukaryotic cells. These acid hydrolases carry mannose 6-phosphate recognition markers on theirN-linked oligosaccharides that are recognized by two distinct MPRs: the cation-dependent mannose 6-phosphate receptor and the insulin-like growth factor II/cation-independent mannose 6-phosphate receptor. Although much has been learned about the MPRs, it is unclear how these receptors interact with the highly diverse population of lysosomal enzymes. It is known that the terminal mannose 6-phosphate is essential for receptor binding. However, the results from several studies using synthetic oligosaccharides indicate that the binding site encompasses at least two sugars of the oligosaccharide. We now report the structure of the soluble extracytoplasmic domain of a glycosylation-deficient form of the bovine cation-dependent mannose 6-phosphate receptor complexed to pentamannosyl phosphate. This construct consists of the amino-terminal 154 amino acids (excluding the signal sequence) with glutamine substituted for asparagine at positions 31, 57, 68, and 87. The binding site of the receptor encompasses the phosphate group plus three of the five mannose rings of pentamannosyl phosphate. Receptor specificity for mannose arises from protein contacts with the 2-hydroxyl on the terminal mannose ring adjacent to the phosphate group. Glycosidic linkage preference originates from the minimization of unfavorable interactions between the ligand and receptor. The biogenesis of lysosomes is an essential component of the degradative machinery of the cell and is mediated in part by the mannose 6-phosphate receptors (MPRs). 1The abbreviations used are: MPRmannose 6-phosphate receptorMan-6-Pmannose 6-phosphateCD-MPRcation-dependent mannose 6-phosphate receptorP-MPO4-6-mannose1The abbreviations used are: MPRmannose 6-phosphate receptorMan-6-Pmannose 6-phosphateCD-MPRcation-dependent mannose 6-phosphate receptorP-MPO4-6-mannose Soluble acid hydrolases are synthesized in the rough endoplasmic reticulum where they undergo N-glycosylation along with other secreted proteins. However, in the Golgi, these acid hydrolases acquire a recognition marker on their N-linked oligosaccharides, mannose 6-phosphate (Man-6-P), which serves as a high affinity ligand for the MPRs. The MPR-hydrolase complexes are then transported to a prelysosomal compartment where the acidic pH of the compartment causes the MPR to release the hydrolase. The acid hydrolase is subsequently packaged into lysosomes, whereas the receptor is free to cycle back to the Golgi or move to the plasma membrane (1Kornfeld S. Annu. Rev. Biochem. 1992; 61: 307-330Crossref PubMed Scopus (922) Google Scholar, 2Munier-Lehmann H. Mauxion F. Hoflack B. Biochem. Soc. Trans. 1996; 24: 133-136Crossref PubMed Scopus (45) Google Scholar, 3von Figura K. Hasilik A. Annu. Rev. Biochem. 1986; 55: 167-193Crossref PubMed Scopus (633) Google Scholar). mannose 6-phosphate receptor mannose 6-phosphate cation-dependent mannose 6-phosphate receptor PO4-6-mannose mannose 6-phosphate receptor mannose 6-phosphate cation-dependent mannose 6-phosphate receptor PO4-6-mannose Two integral membrane glycoproteins, the 46-kDa cation-dependent MPR (CD-MPR) and the 300-kDa insulin-like growth factor-II/cation-independent MPR, have been identified that function in the recognition of Man-6-P-containing proteins. Recent studies have demonstrated that both MPRs are required for the efficient targeting of lysosomal enzymes to the lysosome (4Koster A. Saftig P. Matzner U. von Figura K. Peters C. Pohlmann R. EMBO J. 1993; 12: 5219-5223Crossref PubMed Scopus (77) Google Scholar, 5Ludwig T. Munier-Lehmann H. Bauer U. Hollinshead M. Ovitt C. Lobel P. Hoflack B. EMBO J. 1994; 13: 3430-3437Crossref PubMed Scopus (131) Google Scholar). Although the two MPRs are both capable of high affinity binding of phosphomannosyl residues, they exhibit only limited (∼24%) sequence identity between their extracytoplasmic ligand binding regions (6Lobel P. Dahms N.M. Kornfeld S. J. Biol. Chem. 1988; 263: 2563-2570Abstract Full Text PDF PubMed Google Scholar, 7Roberts D.L. Weix D.J. Dahms N.M. Kim J.-J.P. Cell. 1998; 93: 639-648Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). Over the last 10 years, significant progress has been made in understanding the specificity of carbohydrate recognition by the MPRs. Inhibition studies using chemically synthesized oligomannosides or neoglycoproteins have shown that the presence of Man-6-P at a terminal position represents the major determinant of receptor binding (8Distler J.J. Guo J.F. Jourdian G.W. Srivastava O.P. Hindsgaul O. J. Biol. Chem. 1991; 266: 21687-21692Abstract Full Text PDF PubMed Google Scholar, 9Tomoda H. Ohsumi Y. Ichikawa Y. Srivastava O.P. Kishimoto Y. Lee Y.C. Carbohyd. Res. 1991; 213: 37-46Crossref PubMed Scopus (20) Google Scholar). A similar study using monosaccharides that differed from Man-6-P by a single substituent demonstrated that the phosphate group and the axial 2-hydroxyl of mannose are critical for receptor binding (10Tong P.Y. Kornfeld S. J. Biol. Chem. 1989; 264: 7970-7975Abstract Full Text PDF PubMed Google Scholar). Chemical modifications (11Stein M. Meyer H.E. Hasilik A. von Figura K. Biol. Chem. Hoppe-Seyler. 1987; 368: 927-936Crossref PubMed Scopus (52) Google Scholar) and site-directed mutagenesis (12Wendland M. Waheed A. von Figura K. Pohlmann R. J. Biol. Chem. 1991; 266: 2917-2923Abstract Full Text PDF PubMed Google Scholar, 13Dahms N.M. Rose P.A. Molkentin J.D. Zhang Y. Brzycki M.A. J. Biol. Chem. 1993; 268: 5457-5463Abstract Full Text PDF PubMed Google Scholar) studies have been conducted to begin to identify the structural determinants of the MPRs that are critical for carbohydrate recognition. An arginine residue has been identified that is conserved in the Man-6-P binding sites of both MPRs and that when changed to either a conservative (Lys) or nonconservative (Ala) amino acid results in the loss of ligand binding activity. We have recently solved the structure of a glycosylation-deficient form of the extracytoplasmic domain of the CD-MPR (Asn81/STOP155) complexed with Man-6-P (1M6P) which has confirmed the importance of this conserved arginine residue and has identified additional residues surrounding the ligand in the binding pocket (7Roberts D.L. Weix D.J. Dahms N.M. Kim J.-J.P. Cell. 1998; 93: 639-648Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). Despite these recent findings, it remains to be determined how the MPRs interact with newly synthesized acid hydrolases, a heterogeneous population of more than 40 enzymes that differ in a number of properties including the extent of phosphorylation of theirN-linked oligosaccharide chains. Although it is clear that the terminal Man-6-P is the major determinant of receptor binding, several studies indicate that the MPRs recognize an extended oligosaccharide structure, which includes the Man-6-Pα1,2Man sequence, to achieve high affinity binding (8Distler J.J. Guo J.F. Jourdian G.W. Srivastava O.P. Hindsgaul O. J. Biol. Chem. 1991; 266: 21687-21692Abstract Full Text PDF PubMed Google Scholar, 9Tomoda H. Ohsumi Y. Ichikawa Y. Srivastava O.P. Kishimoto Y. Lee Y.C. Carbohyd. Res. 1991; 213: 37-46Crossref PubMed Scopus (20) Google Scholar, 14Natowicz M. Hallett D.W. Frier C. Chi M. Schlesinger P.H. Baenziger J.U. J. Cell Biol. 1983; 96: 915-919Crossref PubMed Scopus (18) Google Scholar, 15Varki A. Kornfeld S. J. Biol. Chem. 1980; 255: 10847-10858Abstract Full Text PDF PubMed Google Scholar). To further clarify the structural basis by which the MPRs recognize phosphorylated oligosaccharides, we have determined the three-dimensional structure of the extracytoplasmic domain of the CD-MPR complexed with pentamannosyl phosphate. All chemicals unless otherwise specified were purchased from Sigma. Phosphomannan from Hansenula holstiiwas the kind gift of Dr. M. E. Slodki of the Northern Regional Research Center (Peoria, IL). Penta-d-mannose 6-monophosphate [α-d-Man6PO4(1,3)-α-d-Man(1,3)-α-d-Man(1,3)-α-d-Man(1,2)-α-d-Man] was prepared from the high molecular weight phosphomannan of H. holstii (Y.2448) as described previously (16Bretthauer R.K. Kaczorowski G.J. Weise M.J. Biochemistry. 1973; 12: 1251-1256Crossref PubMed Scopus (62) Google Scholar). The glycosylation-deficient extracytoplasmic domain (Asn81/STOP155) of the bovine CD-MPR was generated as described previously (17Zhang Y. Dahms N.M. Biochem. J. 1993; 295: 841-848Crossref PubMed Scopus (27) Google Scholar) and expressed in Trichoplusia ni 5B1–4 (High Five) insect cells. Recombinant Asn81/STOP155 was purified to near homogeneity by pentamannosyl phosphate-agarose affinity chromatography as described previously (18Marron-Terada P.G. Bollinger K.E. Dahms N.M. Biochemistry. 1998; 37: 17223-17229Crossref PubMed Scopus (20) Google Scholar). CD-MPR was extensively dialyzed against buffer containing 150 mm NaCl, 10 mmMnCl2, 5 mm β-glycerophosphate, and 50 mm imidazole, pH 6.4, to remove the Man-6-P present from the above purification. The protein was then concentrated to ∼1.8 mg/ml prior to incubation overnight at 4 °C in the presence of 10 mm pentamannosyl phosphate. Crystallization was carried out at 19 °C by vapor diffusion using the hanging drop method (19McPherson A. Eur. J. Biochem. 1990; 189: 1-23Crossref PubMed Scopus (342) Google Scholar) by mixing equal volumes (1 μl:1 μl) of the purified bovine CD-MPR (10 mg/ml) with the precipitating solution ((25% (w/v) poly(ethylene glycol) 5000 monomethyl ether (Fluka, Milwaukee, WI), 0.2 mammonium acetate in 0.1 m cacodylate buffer pH 6.5)). The crystal was mounted in a thin-walled glass capillary tube, and diffraction data were collected at 4 °C on an R-axis IIC image plate detector system with a Rigaku RU200 rotating anode generator operating at 50 kV and 100 mA with a graphite monochromator. Still photographs indicated that the crystal belongs to the monoclinic space group P21 with unit cell parametersa = 42.8 Å, b = 79.3 Å,c = 55.6 Å, and β = 100.3 °. Assuming two monomers/asymmetric unit, the calculated Matthews' coefficient is 2.7 Å3/Da (20Matthews B.W. J. Mol. Biol. 1968; 33: 491-497Crossref PubMed Scopus (7893) Google Scholar). A single native data set was collected to 1.85 Å resolution at 4 °C. The diffraction data were processed with the DENZO package (21Otwinowski Z. Minor W. Methods Enzymol. 1997; 276: 307-326Crossref Scopus (38252) Google Scholar), and the statistics are given in TableI.Table IData collection statisticsParametersResolution range (Å)40–1.85 (1.90–1.85)aNumbers in parentheses are for the highest resolution shell of the data.Total number of reflections48273Unique reflections28822R sym (%)5.1 (29.2)Completeness (%)85 (62.3)Space groupP21Number of molecules/asym. unit2Unit cell dimensionsa (Å)42.8b (Å)79.3c (Å)55.6β (°)100.3Final R factor (%)21.1R free (%)25.2Number of water molecules172Deviations in rms geometryBond length (Å)0.006Bond angles (°)1.6Average B factors (Å2)Main chain25.9Side chain28.2Pentamannosyl Phosphate38.5N-acetylglucosamine61.6Mn+2 Monomer A73.1 Monomer B54.1 Water38.4a Numbers in parentheses are for the highest resolution shell of the data. Open table in a new tab The structure of bovine CD-MPR bound to pentamannosyl phosphate was solved by molecular replacement (22Rossman M.G. Blow D.M. Acta Crystallogr. 1962; 15: 24-31Crossref Google Scholar) using the refined crystal structure of the CD-MPR dimer bound to Man-6-P (7Roberts D.L. Weix D.J. Dahms N.M. Kim J.-J.P. Cell. 1998; 93: 639-648Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar) as the search model and the X-PLOR program package (23Brunger A.T. X-PLOR v.3.1 Instruction Manual. Yale University Press, New Haven, CT1992Google Scholar). Rotation and translation searches were performed using all diffraction data between 15 and 4 Å resolution. The rotation search produced two peaks that are related by the 2-fold axis of the dimer molecule that corresponds to the noncrystallographic symmetry in the asymmetric unit (Table II). The translation search was carried out using a solution with the highest rotation function value of 6.37. This gave an initial R factor of 34.7%. Ten cycles of rigid body refinement were subsequently carried out treating each monomer (A and B) as a rigid unit. This lowered the R value to 33.0% using 10 to 3 Å resolution data.Table IIMolecular replacement solutionsEulerian anglesRotation functionPatterson correlationθ1θ2θ3degrees95.2072.50137.556.370.347260.5490.00218.876.010.33691.0375.00148.974.970.346Translation functionVector (along crystallographic axes)Peak height/ςÅa = 12.81c = 13.6722.64 Open table in a new tab At this stage, the structure was refined using all data to 1.8 Å resolution using X-PLOR with manual adjustments between refinement cycles on a Silicon Graphics workstation using Turbo graphics software (24Roussel Cambillau Turbo, Version 4.2. Biographics, LCCMB, Marseille, France1994Google Scholar). In general, one round of refinement consisted of Powell positional refinement, simulated annealing from 3000 to 300 K, and a second positional refinement. Temperature factor refinement was also employed in the later cycles. Bulk solvent correction for the reflection data was applied in later cycles of refinement. After each round of refinement, both Fo − Fcand 2Fo − Fc difference Fourier maps were calculated. When attempting to clarify residues 38–43, which were not well defined in the initial electron density map, alanine residues were initially substituted. These residues were changed to the appropriate native residues upon improvement of the electron density maps. The individual mannose rings of pentamannosyl phosphate were added at various stages of refinement based on the clarity of the electron density map. Two N-acetylglucosamine molecules were fitted to each monomer mid-way through the refinement procedure. Finally, water molecules were assigned when densities greater than 3.5 ς and within 3.2 Å of a potential hydrogen-bonding partner were observed in the Fo − Fc electron density map. The bovine CD-MPR consists of a 28-residue amino-terminal signal sequence, a 159-residue extracytoplasmic domain, a single 25-residue transmembrane domain, and a 67-residue carboxyl-terminal domain (25Dahms N.M. Lobel P. Breitmeyer J. Chirgwin J.M. Kornfeld S. Cell. 1987; 50: 181-192Abstract Full Text PDF PubMed Scopus (95) Google Scholar). The CD-MPR exists as a dimer (7Roberts D.L. Weix D.J. Dahms N.M. Kim J.-J.P. Cell. 1998; 93: 639-648Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 26Li M. Distler J.J. Jourdian G.W. Arch. Biochem. Biophys. 1990; 283: 150-157Crossref PubMed Scopus (17) Google Scholar, 27Punnonen E.L. Wilke T. von Figura K. Hille-Rehfeld A. Eur. J. Biochem. 1996; 237: 809-818Crossref PubMed Scopus (17) Google Scholar) and is glycosylated at four out of its five potentialN-glycosylation sites (17Zhang Y. Dahms N.M. Biochem. J. 1993; 295: 841-848Crossref PubMed Scopus (27) Google Scholar). In many species the presence of divalent cations, such as Mn+2, enhance the binding affinity of the receptor (10Tong P.Y. Kornfeld S. J. Biol. Chem. 1989; 264: 7970-7975Abstract Full Text PDF PubMed Google Scholar, 26Li M. Distler J.J. Jourdian G.W. Arch. Biochem. Biophys. 1990; 283: 150-157Crossref PubMed Scopus (17) Google Scholar, 28Ma Z. Grubb J.H. Sly W.S. J. Biol. Chem. 1992; 267: 19017-19022Abstract Full Text PDF PubMed Google Scholar). We have previously shown that a truncated, glycosylation-deficient form of the bovine CD-MPR (Asn81/STOP155) binds β-glucuronidase with an affinity identical to that of the full-length wild-type receptor (18Marron-Terada P.G. Bollinger K.E. Dahms N.M. Biochemistry. 1998; 37: 17223-17229Crossref PubMed Scopus (20) Google Scholar). Asn81/STOP155, which consists of residues 1–154 of the mature protein, has four out of its five potentialN-glycosylation sites removed by replacing the asparagine residues at positions 31, 57, 68, and 87 with glutamine and utilizes the remaining N-glycosylation site at position 81 (17Zhang Y. Dahms N.M. Biochem. J. 1993; 295: 841-848Crossref PubMed Scopus (27) Google Scholar, 18Marron-Terada P.G. Bollinger K.E. Dahms N.M. Biochemistry. 1998; 37: 17223-17229Crossref PubMed Scopus (20) Google Scholar). In the current study, we have determined and refined the structure of Asn81/STOP155 complexed with pentamannosyl phosphate [α-d-Man-6-P-(1,3)-α-d-Man(1,3)-α-d-Man(1,3)-α-d-Man(1,2)-α-d-Man], an oligosaccharide that has been used extensively to purify the MPRs by affinity chromatography (29Hoflack B. Kornfeld S. J. Biol. Chem. 1985; 260: 12008-12014Abstract Full Text PDF PubMed Google Scholar). The structure of the bovine Asn81/STOP155 CD-MPR bound to pentamannosyl phosphate has been refined to 1.85 Å with good geometry. Table I summarizes the data collection and refinement statistics. Analysis of the final structure by PROCHECK (30Laskowski R.A. MacArthur M.W. Moss D.S. Thornton J.M. J. Appl. Crystallogr. 1993; 26: 283-291Crossref Google Scholar) yielded all nonproline and nonglycine residues in either the most favored or additionally allowed regions of the Ramachandran plot. The first residue with visible electron density is Glu3, and the electron density for both peptide chains of the dimer is continuous through the carboxyl-terminal Ser154. Only the twoN-acetylglucosamine residues of the oligosaccharide chain at Asn81 are visible, suggesting that the remainder of the oligosaccharide is flexible. Although the exact structure of this oligosaccharide is not known, removal of the carbohydrate by endo-β-N-acetylglucosaminidase H 2N. M. Dahms, unpublished results. demonstrates that the oligosaccharide contains two N-acetylglucosamine and at least four mannose residues. A comparison of the two peptide chains of the dimer reveals that they are virtually identical with a root mean square deviation between backbone atoms of 0.55 Å for the entire polypeptide chain. We have recently reported the structure of the bovine CD-MPR bound to Man-6-P (7Roberts D.L. Weix D.J. Dahms N.M. Kim J.-J.P. Cell. 1998; 93: 639-648Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). The overall structure of the CD-MPR bound to pentamannosyl phosphate is very similar to that of the receptor bound to Man-6-P (Fig. 1). The root mean square deviation between the corresponding monomers of the two structures, excluding loop A, is 0.66 Å and demonstrates that the structures are virtually identical. The protein is comprised of an amino-terminal α-helix that leads into a four stranded, antiparallel β-sheet oriented orthogonally over another β-sheet composed of the remaining five β-strands of the protein. The loops between strands 1 and 2 (loop A), 3 and 4 (loop B), and 6 and 7 (loop C) enclose the ligand binding pocket. The six cysteine residues of the molecule are involved in three disulfide bonds (Cys6-Cys52, Cys106-Cys141, and Cys119-Cys153). The most striking difference between these structures lies in loop A (residues 38–43). The previously reported structure utilizing the smaller Man-6-P ligand showed that this region was not well defined, indicating its dynamic nature. In the presence of the larger ligand, loop A adopts a more ordered structure, as demonstrated by its clearly discernable electron density, and is drawn toward the binding pocket by 1–3 Å. The C loop containing residues 102–105, which is located in the region near the phosphate in the binding pocket, has also shifted toward the phosphate group, and the main chain amide group of Asn104 has rotated by approximately 80 ° (ψ= 28 from ψ= -50), thereby altering some of the contacts between ligand and receptor. Previous inhibition studies have indicated that the MPRs recognize at least two mannose residues of the oligosaccharide chain (8Distler J.J. Guo J.F. Jourdian G.W. Srivastava O.P. Hindsgaul O. J. Biol. Chem. 1991; 266: 21687-21692Abstract Full Text PDF PubMed Google Scholar, 9Tomoda H. Ohsumi Y. Ichikawa Y. Srivastava O.P. Kishimoto Y. Lee Y.C. Carbohyd. Res. 1991; 213: 37-46Crossref PubMed Scopus (20) Google Scholar). To analyze the interaction of the MPRs with an oligosaccharide, we have now solved the structure of the Asn81/STOP155 CD-MPR complexed to pentamannosyl phosphate. Fig. 2depicts the electron density map (2Fo − Fc) of the ligand contoured at 1 ς. The phosphate group and terminal three sugar rings exhibit clearly observable electron density. The electron density of the fourth mannose ring is only partially visible at the 1 ς level. Modeling of a sugar ring into this region results in a slight (0.4, 0.1%) increase in R andR free values upon refinement. This ring also appeared to make no contacts with the polypeptide, and therefore, it was omitted from the final structure. In this structure we show the phosphate moiety is essentially buried in the protein with only 12 Å2 (8%) solvent accessible. The mannose rings become progressively more solvent-accessible as their location is more distal (terminal mannose (I) = 3%, penultimate mannose (II) = 38%, and prepenultimate mannose (III) = 62%) from the phosphate group. The prepenultimate mannose ring extends to the protein surface (Figs.3 and4).Figure 3A, stereo diagram of the ligand binding pocket of CD-MPR complexed to pentamannosyl phosphate. The ligand moiety is shaded, and the mannose rings are numbered as discussed in the text. B, an enlarged view of the Mn+2 coordination found in the B monomer.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 4Diagram showing the accessible area of the bound ligand. Molecular surfaces were generated for the terminal three sugar residues of pentamannosyl phosphate (solid yellow) as well as CD-MPR (red mesh). Only surfaces within 1.4 Å of each other are shown. The view shown in Bis rotated 90° about the vertical axis from that shown inA.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Fig. 5 shows the various contacts between pentamannosyl phosphate and the CD-MPR (Fig. 5 A) and between Man-6-P and the CD-MPR (Fig. 5 B). The interactions between the polypeptide and the terminal phosphomannose moiety are essentially the same in the two structures, except there is a minor difference in the distance between the C-4 hydroxyl of the terminal sugar and the terminal NH of the guanidine group of Arg135. From comparison of the bonding schemes we may conclude that the presence of additional mannose rings does not affect the binding of the terminal residue. However, as discussed above, the presence of the additional rings results in a slight collapse of the binding pocket because of the change in positioning of loops A and C. Loop A is tethered in place by residues Asp43 and Tyr45, which make hydrogen bond contacts with the penultimate sugar ring. The structures of several other mannose binding lectins have been determined in both the presence of a monosaccharide as well as a di- or trisaccharide. Concanavalin A is an extensively studied legume lectin that specifically binds the trimannoside core found in allN-linked glycans. Naismith and Field (31Naismith J.H. Field R.A. J. Biol. Chem. 1996; 271: 972-976Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar) reported the structure of a concanavalin A-trimannoside complex (2.3 Å resolution); when this structure was compared with the structure of concanavalin A complexed to methyl α-mannoside at 2.0 Å resolution (32Naismith J.H. Emmerich C. Habash J. Harrop S.J. Helliwell J.R. Hunter W.N. Raftery J. Kalb-Gilboa J. Yariv J. Acta Crystallogr. Sect. D Biol. Crystallogr. 1994; 50: 847-858Crossref PubMed Scopus (164) Google Scholar), the root mean square deviation between the two structures for all cα atoms was 0.28 Å (31Naismith J.H. Field R.A. J. Biol. Chem. 1996; 271: 972-976Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar). It was observed that residues 118–123 as well as the loops at residues 161 and 204 remained disordered in the presence of the trisaccharide (31Naismith J.H. Field R.A. J. Biol. Chem. 1996; 271: 972-976Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar). However, none of these regions are involved in binding ligand unlike the case of loop A in the CD-MPR, which becomes more ordered in the presence of an oligosaccharide and does in fact contain residues that interact with the longer ligand. In the case of the legume lectins, isolectin I of Lathyrus ochrus and pea lectin, there is no discernable change in structure upon binding a tri- or disaccharide compared with a monosaccharide (33Bourne Y. Rouge P. Cambillau C. J. Biol. Chem. 1990; 265: 18161-18165Abstract Full Text PDF PubMed Google Scholar, 34Rini J.M. Hardman K.D. Einspahr H. Suddath F.L. Carver J.P. J. Biol. Chem. 1993; 268: 10126-10132Abstract Full Text PDF PubMed Google Scholar). Therefore, when compared with other mannose binding lectins, the CD-MPR appears to be distinct in that the presence of an oligosaccharide orders the binding site. A bound oligosaccharide may have a greater influence on the binding site structure of CD-MPR compared with other mannose binding lectins because of the depth of the binding pocket. The binding site of CD-MPR penetrates into the molecule, whereas the other mannose binding lectins interact with the oligosaccharide on the surface. In the case ofErythrina corallodendron lectin, only the penultimate sugar makes one direct hydrogen-bond contact with the protein (35Shaanan B. Lis H. Sharon N. Science. 1991; 254: 862-866Crossref PubMed Scopus (264) Google Scholar). On the other hand, in the structure of isolectin I of L. ochrus, the prepenultimate and penultimate sugars of a trisaccharide do not directly contact the protein. Only the terminal mannose establishes direct hydrogen bonds to this lectin, whereas the remaining sugar interactions are mediated through water molecules (33Bourne Y. Rouge P. Cambillau C. J. Biol. Chem. 1990; 265: 18161-18165Abstract Full Text PDF PubMed Google Scholar). Although pea lectin was crystallized in the presence of a trisaccharide, only one sugar moiety exhibits visible electron density (34Rini J.M. Hardman K.D. Einspahr H. Suddath F.L. Carver J.P. J. Biol. Chem. 1993; 268: 10126-10132Abstract Full Text PDF PubMed Google Scholar). Concanavalin A contacts three sugar residues upon binding, but it does so along the surface of the protein in a shallow groove rather than a cleft (31Naismith J.H. Field R.A. J. Biol. Chem. 1996; 271: 972-976Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar) as do many of the legume isolectin I lectins (36Loris R. Hamelryck T. Bouckaert J. Wyns L. Biochim. Biophys. Acta. 1998; 1383: 9-36Crossref PubMed Scopus (466) Google Scholar). The binding site architecture of the CD-MPR appears to be unique among the lectins. The binding site is a deep cleft with the phosphate and terminal mannose positioned against the bottom. The bottom of the cleft is formed by residues Gln66, Arg111, and Tyr143. These residues are located in β-strands 3, 7, and 9, respectively. The sides of the cleft are formed by residues in loops A (Asp43 and Tyr45), B (Gln68), and C (Asp103, Asn104, and His105) in addition to the loop connecting β-strands 8 and 9 (Arg135) (Fig. 3). Our studies show that this binding site configuration allows for protein contacts to be made to three mannose rings. As previously stated, Asn81/STOP155 is a glycosylation-deficient form of the receptor in which Gln68 has replaced the asparagine residue found in the wild-type receptor. It is unclear whether the shorter asparagine side chain at this position in the wild-type CD-MPR will provide this interaction. However," @default.
• W2021989115 created "2016-06-24" @default.
• W2021989115 creator A5022627653 @default.
• W2021989115 creator A5022948595 @default.
• W2021989115 creator A5044750614 @default.
• W2021989115 creator A5057209439 @default.
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• W2021989115 date "1999-10-01" @default.
• W2021989115 modified "2023-10-16" @default.
• W2021989115 title "Structural Basis for Recognition of Phosphorylated High Mannose Oligosaccharides by the Cation-dependent Mannose 6-Phosphate Receptor" @default.
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