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. Author manuscript; available in PMC: 2012 Feb 25.
Published in final edited form as: J Mol Biol. 2010 Dec 23;406(3):454–466. doi: 10.1016/j.jmb.2010.12.026

Fig. 6.

Fig. 6

Model of Ub degradation by IDE and nestin-mediated regulation. (A) Three-step mechanism of Ub degradation by IDE. (1) The flexible C-terminal tail of Ub swings toward the catalytic cleft without considerable disruption of the Ub fold. (2) The exosite binds the N-terminus of Ub and facilitates in slight unfolding of the peptide and alignment of residues 72 and 73 at the active site. (3) IDE may further degrade the Ub protein processively along the C- to N-terminal direction, depending on Ub instability. (B) Inhibition of Ub degradation by nestin-mediated modulation of the open/closed state of IDE. IDE exists in equilibrium between an open and closed state. While IDE is open, both Ub and small substrates may enter the chamber. However, nestin binds to the exterior surface of IDE, which likely restricts IDE to a partially open state. This partially open state provides enough entry space for small substrates. Ub is denied access to the chamber and is thus not cleaved.