Proteome-wide analysis of chaperone-mediated autophagy targeting motifs
PLoS Biol. 2019-05-31; 17(5): e3000301
DOI: 10.1371/journal.pbio.3000301
Lire sur PubMed
Kirchner P(1)(2), Bourdenx M(1)(2), Madrigal-Matute J(1)(2), Tiano S(1)(2), Diaz A(1)(2), Bartholdy BA(3), Will B(2)(3)(4), Cuervo AM(1)(2)(4).
Author information:
(1)Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
(2)Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, United States of America.
(3)Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America.
(4)Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America.
Chaperone-mediated autophagy (CMA) contributes to the lysosomal degradation of a
selective subset of proteins. Selectivity lies in the chaperone heat shock
cognate 71 kDa protein (HSC70) recognizing a pentapeptide motif (KFERQ-like
motif) in the protein sequence essential for subsequent targeting and degradation
of CMA substrates in lysosomes. Interest in CMA is growing due to its recently
identified regulatory roles in metabolism, differentiation, cell cycle, and its
malfunctioning in aging and conditions such as cancer, neurodegeneration, or
diabetes. Identification of the subset of the proteome amenable to CMA
degradation could further expand our understanding of the pathophysiological
relevance of this form of autophagy. To that effect, we have performed an in
silico screen for KFERQ-like motifs across proteomes of several species. We have
found that KFERQ-like motifs are more frequently located in solvent-exposed
regions of proteins, and that the position of acidic and hydrophobic residues in
the motif plays the most important role in motif construction. Cross-species
comparison of proteomes revealed higher motif conservation in CMA-proficient
species. The tools developed in this work have also allowed us to analyze the
enrichment of motif-containing proteins in biological processes on an
unprecedented scale and discover a previously unknown association between the
type and combination of KFERQ-like motifs in proteins and their participation in
specific biological processes. To facilitate further analysis by the scientific
community, we have developed a free web-based resource (KFERQ finder) for direct
identification of KFERQ-like motifs in any protein sequence. This resource will
contribute to accelerating understanding of the physiological relevance of CMA.
Conflict of interest statement: The authors have declared that no competing
interests exist based on the content of the submitted manuscript.