Biology

Proteome-wide analysis of chaperone-mediated autophagy targeting motifs

by Philipp Kirchner, Mathieu Bourdenx, Julio Madrigal-Matute, Simoni Tiano, Antonio Diaz, Boris A. Bartholdy, Britta Will, Ana Maria Cuervo

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.

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