Conformational analysis of pentapeptide sequences matching a proposed recognition motif for lysosomal degradation.
A selective pathway for the degradation of specific long-lived cytosolic proteins is activated in response to starvation in vivo or to serum withdrawal from cultured cells. It involves recognition of a targeting motif by a member of the hsp70 family. A 5-residue targeting motif has been proposed on the basis of sequence comparisons. We investigate whether there is any structural basis for this motif being the true recognition signal. We examine the conformations of four motif peptides in proteins that are either known to be serum regulated or are from related vertebrate species, and two equivalent peptides in bacterial proteins that closely resemble other regulated proteins. Our studies show that all the motif sequences are located near the ends of surface helices 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 extended peptide chains. Furthermore, recognition by these proteins generally requires a specific ordering of key residues, yet the motif implies a largely order-independent sequence characterized by residue type only. We conclude that the proposed motif is unlikely to be the true targeting signal for lysosomal degradation unless additional factors apply.
Gorinsky
B
B
Department of Crystallography, Birkbeck College, London, UK.
Laskowski
R A
RA
Lee
D A
DA
Bomford
A
A
D000595:Amino Acid Sequence; D000818:Animals; D002415:Cats; D002417:Cattle; D016208:Databases, Factual; D004926:Escherichia coli / Q000737:chemistry; D001411:Geobacillus stearothermophilus / Q000737:chemistry; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D021382:Protein Sorting Signals / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry; D011817:Rabbits
D018840:HSP70 Heat-Shock Proteins; D009842:Oligopeptides; D021382:Protein Sorting Signals; D011506:Proteins