Schematized Michaelis-Menten kinetics of substrate degradation illustrating two regimes of substrate concentration: [S] is well below the KM (A) and well above the KM (B). If [S] is 100-fold below the KM, then the degradation rate is ~1% of the maximum velocity (A). Scaffolding adaptors can tether substrates to the protease and increase local concentration by this leashing. As shown in B, a tether length of ~25 residues would result in constraining a single molecule to a volume of ~10−21 L, which yields an effective concentration of ~1 mM, sufficient to drive degradation at the maximum rate. (C) Substrate recognition by the adaptor must be of at least moderate affinity in order to ensure specificity. However, excessively tight binding of the adaptor restricts delivery of the substrate and inhibits overall degradation.