XXXX - and @entity369 -rich peptides constitute a novel class of allosteric inhibitors of proteasome activity.

@entity1 @entity45659 @entity7738 @entity4284 @entity2733 @entity1521 @entity375 @entity369
Substrate-specific inhibition of the proteasome has been unachievable despite great interest in proteasome inhibitors as drugs. Recent studies demonstrated that @entity45659 , a natural @entity1521 - and @entity369 -rich antibacterial peptide, stimulates angiogenesis and inhibits inflammatory responses by specifically blocking degradation of @entity4284 and @entity7738 by the proteasome. However, molecular events involved in the @entity45659 -proteasome interaction have not been elucidated. Here we show that @entity45659 is a noncompetitive and reversible inhibitor of the proteasome function. This effect is achieved by a unique allosteric mechanism allowing for specific inhibition of degradation of selected proteins without affecting total proteasome-dependent proteolysis. Atomic force microscopy (AFM) studies demonstrate that 20S and 26S proteasomes treated with @entity45659 or its derivatives exhibit serious perturbations in their structure and their normal allosteric movements. These effects are universal for proteasomes from @entity375 to @entity1 . The shortest functional sequence derived from @entity45659 still showing the allosteric inhibitory effect consists of eleven @entity2733 -terminal residues containing essential three @entity2733 -terminal arginines. The noncompetitive and reversible in vitro action of @entity45659 and its truncated derivatives is matched by the ability of the peptides to induce angiogenesis in vivo. We postulate that @entity45659 changes conformational dynamics of the proteasomes by interactions with the noncatalytic subunit alpha7 in a way that prevents the enzyme from cleaving the substrates of unique structural constraints.
