PMID- 31150375 OWN - NLM STAT- MEDLINE DCOM- 20191216 LR - 20220204 IS - 1545-7885 (Electronic) IS - 1544-9173 (Print) IS - 1544-9173 (Linking) VI - 17 IP - 5 DP - 2019 May TI - Proteome-wide analysis of chaperone-mediated autophagy targeting motifs. PG - e3000301 LID - 10.1371/journal.pbio.3000301 [doi] LID - e3000301 AB - 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. FAU - Kirchner, Philipp AU - Kirchner P AD - Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America. AD - Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, United States of America. FAU - Bourdenx, Mathieu AU - Bourdenx M AUID- ORCID: 0000-0002-9799-9222 AD - Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America. AD - Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, United States of America. FAU - Madrigal-Matute, Julio AU - Madrigal-Matute J AUID- ORCID: 0000-0002-0894-5450 AD - Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America. AD - Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, United States of America. FAU - Tiano, Simoni AU - Tiano S AD - Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America. AD - Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, United States of America. FAU - Diaz, Antonio AU - Diaz A AD - Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America. AD - Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, United States of America. FAU - Bartholdy, Boris A AU - Bartholdy BA AUID- ORCID: 0000-0002-7401-8591 AD - Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America. FAU - Will, Britta AU - Will B AD - Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, United States of America. AD - Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America. AD - Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America. FAU - Cuervo, Ana Maria AU - Cuervo AM AUID- ORCID: 0000-0002-0771-700X AD - Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, United States of America. AD - Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York, United States of America. AD - Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America. LA - eng GR - U54 NS100717/NS/NINDS NIH HHS/United States GR - R01 AG021904/AG/NIA NIH HHS/United States GR - K01 DK105134/DK/NIDDK NIH HHS/United States GR - R37 AG021904/AG/NIA NIH HHS/United States GR - RF1 AG054108/AG/NIA NIH HHS/United States GR - P30 AG038072/AG/NIA NIH HHS/United States GR - P01 AG031782/AG/NIA NIH HHS/United States GR - R01 DK098408/DK/NIDDK NIH HHS/United States GR - P01 AG017617/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20190531 PL - United States TA - PLoS Biol JT - PLoS biology JID - 101183755 RN - 0 (Proteome) SB - IM EIN - PLoS Biol. 2022 Feb 4;20(2):e3001550. PMID: 35120120 MH - *Amino Acid Motifs MH - Amino Acid Sequence MH - Animals MH - *Chaperone-Mediated Autophagy MH - Conserved Sequence MH - Drosophila melanogaster/genetics MH - Evolution, Molecular MH - Humans MH - Mice MH - NIH 3T3 Cells MH - Proteome/chemistry/*metabolism MH - Saccharomyces cerevisiae/genetics PMC - PMC6561683 COIS- The authors have declared that no competing interests exist based on the content of the submitted manuscript. EDAT- 2019/06/01 06:00 MHDA- 2019/12/18 06:00 PMCR- 2019/05/31 CRDT- 2019/06/01 06:00 PHST- 2018/09/25 00:00 [received] PHST- 2019/05/15 00:00 [accepted] PHST- 2019/06/12 00:00 [revised] PHST- 2019/06/01 06:00 [pubmed] PHST- 2019/12/18 06:00 [medline] PHST- 2019/06/01 06:00 [entrez] PHST- 2019/05/31 00:00 [pmc-release] AID - PBIOLOGY-D-18-00786 [pii] AID - 10.1371/journal.pbio.3000301 [doi] PST - epublish SO - PLoS Biol. 2019 May 31;17(5):e3000301. doi: 10.1371/journal.pbio.3000301. eCollection 2019 May.