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PDBsum entry 2kvb
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Protein transport
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PDB id
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2kvb
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References listed in PDB file
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Key reference
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Title
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Structural basis for recognition of phosphodiester-Containing lysosomal enzymes by the cation-Independent mannose 6-Phosphate receptor.
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Authors
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L.J.Olson,
F.C.Peterson,
A.Castonguay,
R.N.Bohnsack,
M.Kudo,
R.R.Gotschall,
W.M.Canfield,
B.F.Volkman,
N.M.Dahms.
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Ref.
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Proc Natl Acad Sci U S A, 2010,
107,
12493-12498.
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PubMed id
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Abstract
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Mannose 6-phosphate (Man-6-P)-dependent trafficking is vital for normal
development. The biogenesis of lysosomes, a major cellular site of protein,
carbohydrate, and lipid catabolism, depends on the 300-kDa cation-independent
Man-6-P receptor (CI-MPR) that transports newly synthesized acid hydrolases from
the Golgi. The CI-MPR recognizes lysosomal enzymes bearing the Man-6-P
modification, which arises by the addition of GlcNAc-1-phosphate to mannose
residues and subsequent removal of GlcNAc by the uncovering enzyme (UCE). The
CI-MPR also recognizes lysosomal enzymes that elude UCE maturation and instead
display the Man-P-GlcNAc phosphodiester. This ability of the CI-MPR to target
phosphodiester-containing enzymes ensures lysosomal delivery when UCE activity
is deficient. The extracellular region of the CI-MPR is comprised of 15
repetitive domains and contains three distinct Man-6-P binding sites located in
domains 3, 5, and 9, with only domain 5 exhibiting a marked preference for
phosphodiester-containing lysosomal enzymes. To determine how the CI-MPR
recognizes phosphodiesters, the structure of domain 5 was determined by NMR
spectroscopy. Although domain 5 contains only three of the four disulfide bonds
found in the other seven domains whose structures have been determined to date,
it adopts the same fold consisting of a flattened beta-barrel. Structure
determination of domain 5 bound to N-acetylglucosaminyl
6-phosphomethylmannoside, along with mutagenesis studies, revealed the residues
involved in diester recognition, including Y679. These results show the
mechanism by which the CI-MPR recognizes Man-P-GlcNAc-containing ligands and
provides new avenues to investigate the role of phosphodiester-containing
lysosomal enzymes in the biogenesis of lysosomes.
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