CONFORMATIONAL-ANALYSIS OF PENTAPEPTIDE SEQUENCES MATCHING A PROPOSEDRECOGNITION MOTIF FOR LYSOSOMAL DEGRADATION

A selective pathway for the degradation of specific long-lived cytosol ic proteins is activated in response to starvation in vivo or to serum withdrawal from cultured cells. It involves recognition of a targetin g motif by a member of the hsp70 family. A 5-residue targeting motif h as been proposed on the basis of sequence comparisons. We investigate whether there is any structural basis for this motif being the true re cognition signal. We examine the conformations of four motif peptides in proteins that are either known to be serum regulated or are from re lated vertebrate species, and two equivalent peptides in bacterial pro teins that closely resemble other regulated proteins. Our studies show that all the motif sequences are located near the ends of surface hel ices with one or more of the residues buried in the structure, yet it is known that members of the hsp70 family tend to interact with extend ed peptide chains. Furthermore, recognition by these proteins generall y requires a specific ordering of key residues, yet the motif implies a largely order-independent sequence characterised by residue type onl y. We conclude that the proposed motif is unlikely to be the true targ eting signal for lysosomal degradation unless additional factors apply .