8/31/2023 0 Comments Chaperone definition in biologyDice near the N terminus of ribonuclease A. This work focuses on CMA, which degrades single proteins that carry a specific combination of five amino acids, named “KFERQ-motif” after the first of such pentapeptides was discovered by the late J.F. All three share the lysosome as the final catabolic compartment, but their mechanisms for cargo delivery and regulation differ considerably. Three main types of autophagy coexist in most mammalian cells: macroautophagy, chaperone-mediated autophagy (CMA), and microautophagy. Ras-related C3 botulinum toxin substrate 1 RARα,Īutophagy is an essential cellular pathway involved in homeostasis maintenance through degradation and recycling of almost every cellular component, from proteins to lipids and organelles in lysosomes. PH domain leucine-rich repeat-containing protein phosphatase 1 PLIN3, Nuclear factor erythroid 2-related factor 2 PARK7, Nuclear factor of activated T cells NRF-2, Microtubule-associated proteins 1A/1B light chain 3B NFAT, Lysosome-associated membrane protein type 2A LC3-II, Heat shock cognate 71 kDa protein HSP40,ĭnaJ homolog subfamily B member 1 HSP90, Glyceraldehyde-3-phosphate dehydrogenase GFAP, RAC-alpha serine/threonine-protein kinase BLAST,īasic Local Alignment Search Tool Cath A, The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist based on the content of the submitted manuscript. PK was supported by a DFG KI 1992/1-1 postdoctoral fellowship JM-M is supported by postdoctoral fellowship 17POST33650088 from the American Heart Association and is a Leducq fellow of the Transatlantic Network of Excellence (RA15CVD04 award). įunding: This work was supported by grants from the National Institutes of Health AG031782, AG021904, AG038072, DK098408 (to AMC) and the generous support of the JPB Foundation, Rainwaters Foundation, Leducq Foundation, and Robert and Renée Belfer (to AMC). All raw data (individual numerical values that underlie the summary data displayed in main and supplementary figure panels) have been deposited in the publicly available repository GitHub and can be accessed through this link. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ĭata Availability: All relevant data are within the paper and its Supporting Information files. Received: SeptemAccepted: Published: May 31, 2019Ĭopyright: © 2019 Kirchner et al. PLoS Biol 17(5):Īcademic Editor: Anne Simonsen, Institute of Basic Medical Sciences, NORWAY (2019) Proteome-wide analysis of chaperone-mediated autophagy targeting motifs. This resource will contribute to accelerating understanding of the physiological relevance of CMA.Ĭitation: Kirchner P, Bourdenx M, Madrigal-Matute J, Tiano S, Diaz A, Bartholdy BA, et al. 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. 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. Cross-species comparison of proteomes revealed higher motif conservation in CMA-proficient 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. To that effect, we have performed an in silico screen for KFERQ-like motifs across proteomes of several species. 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. 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. 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. Chaperone-mediated autophagy (CMA) contributes to the lysosomal degradation of a selective subset of proteins.
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