Abstract:
:A major puzzle is: are all glycoproteins routed through the ER calnexin pathway irrespective of whether this is required for their correct folding? Calnexin recognizes the terminal Glcalpha1-3Manalpha linkage, formed by trimming of the Glcalpha1-2Glcalpha1-3Glcalpha1-3Manalpha (Glc3Man) unit in Glc3Man9GlcNAc2. Different conformations of this unit have been reported. We have addressed this problem by studying the conformation of a series of N-glycans; i.e. Glc3ManOMe, Glc3Man(4,5,7)GlcNAc2 and Glc1Man9GlcNAc2 using 2D NMR NOESY, ROESY, T-ROESY and residual dipolar coupling experiments in a range of solvents, along with solution molecular dynamics simulations of Glc3ManOMe. Our results show a single conformation for the Glcalpha1-2Glcalpha and Glcalpha1-3Glcalpha linkages, and a major (65%) and a minor (30%) conformer for the Glcalpha1-3Manalpha linkage. Modeling of the binding of Glc1Man9GlcNAc2 to calnexin suggests that it is the minor conformer that is recognized by calnexin. This may be one of the mechanisms for controlling the rate of recruitment of proteins into the calnexin/calreticulin chaperone system and enabling proteins that do not require such assistance for folding to bypass the system. This is the first time evidence has been presented on glycoprotein folding that suggests the process may be optimized to balance the chaperone-assisted and chaperone-independent pathways.
journal_name
J Mol Bioljournal_title
Journal of molecular biologyauthors
Mackeen MM,Almond A,Deschamps M,Cumpstey I,Fairbanks AJ,Tsang C,Rudd PM,Butters TD,Dwek RA,Wormald MRdoi
10.1016/j.jmb.2009.01.043subject
Has Abstractpub_date
2009-03-27 00:00:00pages
335-47issue
2eissn
0022-2836issn
1089-8638pii
S0022-2836(09)00095-3journal_volume
387pub_type
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