Generalizable Compositional Features Influencing the Proteostatic Fates of Polar Low-Complexity Domains
Protein aggregation is associated with a growing list of human diseases. A substantial fraction of proteins in eukaryotic proteomes constitutes a proteostasis network—a collection of proteins that work together to maintain properly folded proteins. One of the overarching functions of the proteostasi...
Gespeichert in:
Veröffentlicht in: | International journal of molecular sciences 2021-08, Vol.22 (16), p.8944 |
---|---|
Hauptverfasser: | , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | |
---|---|
container_issue | 16 |
container_start_page | 8944 |
container_title | International journal of molecular sciences |
container_volume | 22 |
creator | Cascarina, Sean M. Kaplan, Joshua P. Elder, Mikaela R. Brookbank, Lindsey Ross, Eric D. |
description | Protein aggregation is associated with a growing list of human diseases. A substantial fraction of proteins in eukaryotic proteomes constitutes a proteostasis network—a collection of proteins that work together to maintain properly folded proteins. One of the overarching functions of the proteostasis network is the prevention or reversal of protein aggregation. How proteins aggregate in spite of the anti-aggregation activity of the proteostasis machinery is incompletely understood. Exposed hydrophobic patches can trigger degradation by the ubiquitin-proteasome system, a key branch of the proteostasis network. However, in a recent study, we found that model glycine (G)-rich or glutamine/asparagine (Q/N)-rich prion-like domains differ in their susceptibility to detection and degradation by this system. Here, we expand upon this work by examining whether the features controlling the degradation of our model prion-like domains generalize broadly to G-rich and Q/N-rich domains. Experimentally, native yeast G-rich domains in isolation are sensitive to the degradation-promoting effects of hydrophobic residues, whereas native Q/N-rich domains completely resist these effects and tend to aggregate instead. Bioinformatic analyses indicate that native G-rich domains from yeast and humans tend to avoid degradation-promoting features, suggesting that the proteostasis network may act as a form of selection at the molecular level that constrains the sequence space accessible to G-rich domains. However, the sensitivity or resistance of G-rich and Q/N-rich domains, respectively, was not always preserved in their native protein contexts, highlighting that proteins can evolve other sequence features to overcome the intrinsic sensitivity of some LCDs to degradation. |
doi_str_mv | 10.3390/ijms22168944 |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8396281</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2566042908</sourcerecordid><originalsourceid>FETCH-LOGICAL-c389t-a8df91ed8e84fb2d5a9a40b56d9e604cf9fc49b73cdc9780629a6aac3d2d02a63</originalsourceid><addsrcrecordid>eNpdkUFv1DAQhS0EoqVw4wdY4sKBFMd2vPYFCW3ZttJK9NCerYkz2XrlxIvtQMuvx1UrVNAcZqT59PRmHiHvW3YqhGGf_X7KnLdKGylfkONWct4wplYvn81H5E3Oe8a44J15TY6ElLJT0hyT3TnOmCD439AHpOs4HWL2xccZAt0glCVhppfzGBacnZ93tNwivUqxYMwFind0A6UicaRXMUCi2_ireZAJeOfLPT2LE_g5vyWvRggZ3z31E3Kz-Xa9vmi2388v11-3jRPalAb0MJoWB41ajj0fOjAgWd-pwaBi0o1mdNL0K-EGZ1aaKW5AATgx8IFxUOKEfHnUPSz9hIPDudTr7CH5CdK9jeDtv5vZ39pd_Gm1MIrrtgp8fBJI8ceCudjJZ4chwIxxyZZ3qhrhhumKfvgP3ccl1cdVSnFZq4KV-vRIuRRzTjj-NdMy-5CgfZ6g-AN8jZBF</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2624242042</pqid></control><display><type>article</type><title>Generalizable Compositional Features Influencing the Proteostatic Fates of Polar Low-Complexity Domains</title><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>MDPI - Multidisciplinary Digital Publishing Institute</source><source>PubMed Central</source><creator>Cascarina, Sean M. ; Kaplan, Joshua P. ; Elder, Mikaela R. ; Brookbank, Lindsey ; Ross, Eric D.</creator><creatorcontrib>Cascarina, Sean M. ; Kaplan, Joshua P. ; Elder, Mikaela R. ; Brookbank, Lindsey ; Ross, Eric D.</creatorcontrib><description>Protein aggregation is associated with a growing list of human diseases. A substantial fraction of proteins in eukaryotic proteomes constitutes a proteostasis network—a collection of proteins that work together to maintain properly folded proteins. One of the overarching functions of the proteostasis network is the prevention or reversal of protein aggregation. How proteins aggregate in spite of the anti-aggregation activity of the proteostasis machinery is incompletely understood. Exposed hydrophobic patches can trigger degradation by the ubiquitin-proteasome system, a key branch of the proteostasis network. However, in a recent study, we found that model glycine (G)-rich or glutamine/asparagine (Q/N)-rich prion-like domains differ in their susceptibility to detection and degradation by this system. Here, we expand upon this work by examining whether the features controlling the degradation of our model prion-like domains generalize broadly to G-rich and Q/N-rich domains. Experimentally, native yeast G-rich domains in isolation are sensitive to the degradation-promoting effects of hydrophobic residues, whereas native Q/N-rich domains completely resist these effects and tend to aggregate instead. Bioinformatic analyses indicate that native G-rich domains from yeast and humans tend to avoid degradation-promoting features, suggesting that the proteostasis network may act as a form of selection at the molecular level that constrains the sequence space accessible to G-rich domains. However, the sensitivity or resistance of G-rich and Q/N-rich domains, respectively, was not always preserved in their native protein contexts, highlighting that proteins can evolve other sequence features to overcome the intrinsic sensitivity of some LCDs to degradation.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms22168944</identifier><identifier>PMID: 34445649</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Amino acids ; Asparagine ; Biodegradation ; Domains ; Glutamine ; Glycine ; Hydrophobicity ; Libraries ; Mutagenesis ; Proteasomes ; Protein interaction ; Proteins ; Proteomes ; Sensitivity ; Ubiquitin ; Yeast</subject><ispartof>International journal of molecular sciences, 2021-08, Vol.22 (16), p.8944</ispartof><rights>2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 by the authors. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c389t-a8df91ed8e84fb2d5a9a40b56d9e604cf9fc49b73cdc9780629a6aac3d2d02a63</citedby><cites>FETCH-LOGICAL-c389t-a8df91ed8e84fb2d5a9a40b56d9e604cf9fc49b73cdc9780629a6aac3d2d02a63</cites><orcidid>0000-0002-6473-9977</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396281/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396281/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,883,27911,27912,53778,53780</link.rule.ids></links><search><creatorcontrib>Cascarina, Sean M.</creatorcontrib><creatorcontrib>Kaplan, Joshua P.</creatorcontrib><creatorcontrib>Elder, Mikaela R.</creatorcontrib><creatorcontrib>Brookbank, Lindsey</creatorcontrib><creatorcontrib>Ross, Eric D.</creatorcontrib><title>Generalizable Compositional Features Influencing the Proteostatic Fates of Polar Low-Complexity Domains</title><title>International journal of molecular sciences</title><description>Protein aggregation is associated with a growing list of human diseases. A substantial fraction of proteins in eukaryotic proteomes constitutes a proteostasis network—a collection of proteins that work together to maintain properly folded proteins. One of the overarching functions of the proteostasis network is the prevention or reversal of protein aggregation. How proteins aggregate in spite of the anti-aggregation activity of the proteostasis machinery is incompletely understood. Exposed hydrophobic patches can trigger degradation by the ubiquitin-proteasome system, a key branch of the proteostasis network. However, in a recent study, we found that model glycine (G)-rich or glutamine/asparagine (Q/N)-rich prion-like domains differ in their susceptibility to detection and degradation by this system. Here, we expand upon this work by examining whether the features controlling the degradation of our model prion-like domains generalize broadly to G-rich and Q/N-rich domains. Experimentally, native yeast G-rich domains in isolation are sensitive to the degradation-promoting effects of hydrophobic residues, whereas native Q/N-rich domains completely resist these effects and tend to aggregate instead. Bioinformatic analyses indicate that native G-rich domains from yeast and humans tend to avoid degradation-promoting features, suggesting that the proteostasis network may act as a form of selection at the molecular level that constrains the sequence space accessible to G-rich domains. However, the sensitivity or resistance of G-rich and Q/N-rich domains, respectively, was not always preserved in their native protein contexts, highlighting that proteins can evolve other sequence features to overcome the intrinsic sensitivity of some LCDs to degradation.</description><subject>Amino acids</subject><subject>Asparagine</subject><subject>Biodegradation</subject><subject>Domains</subject><subject>Glutamine</subject><subject>Glycine</subject><subject>Hydrophobicity</subject><subject>Libraries</subject><subject>Mutagenesis</subject><subject>Proteasomes</subject><subject>Protein interaction</subject><subject>Proteins</subject><subject>Proteomes</subject><subject>Sensitivity</subject><subject>Ubiquitin</subject><subject>Yeast</subject><issn>1422-0067</issn><issn>1661-6596</issn><issn>1422-0067</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkUFv1DAQhS0EoqVw4wdY4sKBFMd2vPYFCW3ZttJK9NCerYkz2XrlxIvtQMuvx1UrVNAcZqT59PRmHiHvW3YqhGGf_X7KnLdKGylfkONWct4wplYvn81H5E3Oe8a44J15TY6ElLJT0hyT3TnOmCD439AHpOs4HWL2xccZAt0glCVhppfzGBacnZ93tNwivUqxYMwFind0A6UicaRXMUCi2_ireZAJeOfLPT2LE_g5vyWvRggZ3z31E3Kz-Xa9vmi2388v11-3jRPalAb0MJoWB41ajj0fOjAgWd-pwaBi0o1mdNL0K-EGZ1aaKW5AATgx8IFxUOKEfHnUPSz9hIPDudTr7CH5CdK9jeDtv5vZ39pd_Gm1MIrrtgp8fBJI8ceCudjJZ4chwIxxyZZ3qhrhhumKfvgP3ccl1cdVSnFZq4KV-vRIuRRzTjj-NdMy-5CgfZ6g-AN8jZBF</recordid><startdate>20210819</startdate><enddate>20210819</enddate><creator>Cascarina, Sean M.</creator><creator>Kaplan, Joshua P.</creator><creator>Elder, Mikaela R.</creator><creator>Brookbank, Lindsey</creator><creator>Ross, Eric D.</creator><general>MDPI AG</general><general>MDPI</general><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6473-9977</orcidid></search><sort><creationdate>20210819</creationdate><title>Generalizable Compositional Features Influencing the Proteostatic Fates of Polar Low-Complexity Domains</title><author>Cascarina, Sean M. ; Kaplan, Joshua P. ; Elder, Mikaela R. ; Brookbank, Lindsey ; Ross, Eric D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c389t-a8df91ed8e84fb2d5a9a40b56d9e604cf9fc49b73cdc9780629a6aac3d2d02a63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Amino acids</topic><topic>Asparagine</topic><topic>Biodegradation</topic><topic>Domains</topic><topic>Glutamine</topic><topic>Glycine</topic><topic>Hydrophobicity</topic><topic>Libraries</topic><topic>Mutagenesis</topic><topic>Proteasomes</topic><topic>Protein interaction</topic><topic>Proteins</topic><topic>Proteomes</topic><topic>Sensitivity</topic><topic>Ubiquitin</topic><topic>Yeast</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Cascarina, Sean M.</creatorcontrib><creatorcontrib>Kaplan, Joshua P.</creatorcontrib><creatorcontrib>Elder, Mikaela R.</creatorcontrib><creatorcontrib>Brookbank, Lindsey</creatorcontrib><creatorcontrib>Ross, Eric D.</creatorcontrib><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>International journal of molecular sciences</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Cascarina, Sean M.</au><au>Kaplan, Joshua P.</au><au>Elder, Mikaela R.</au><au>Brookbank, Lindsey</au><au>Ross, Eric D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Generalizable Compositional Features Influencing the Proteostatic Fates of Polar Low-Complexity Domains</atitle><jtitle>International journal of molecular sciences</jtitle><date>2021-08-19</date><risdate>2021</risdate><volume>22</volume><issue>16</issue><spage>8944</spage><pages>8944-</pages><issn>1422-0067</issn><issn>1661-6596</issn><eissn>1422-0067</eissn><abstract>Protein aggregation is associated with a growing list of human diseases. A substantial fraction of proteins in eukaryotic proteomes constitutes a proteostasis network—a collection of proteins that work together to maintain properly folded proteins. One of the overarching functions of the proteostasis network is the prevention or reversal of protein aggregation. How proteins aggregate in spite of the anti-aggregation activity of the proteostasis machinery is incompletely understood. Exposed hydrophobic patches can trigger degradation by the ubiquitin-proteasome system, a key branch of the proteostasis network. However, in a recent study, we found that model glycine (G)-rich or glutamine/asparagine (Q/N)-rich prion-like domains differ in their susceptibility to detection and degradation by this system. Here, we expand upon this work by examining whether the features controlling the degradation of our model prion-like domains generalize broadly to G-rich and Q/N-rich domains. Experimentally, native yeast G-rich domains in isolation are sensitive to the degradation-promoting effects of hydrophobic residues, whereas native Q/N-rich domains completely resist these effects and tend to aggregate instead. Bioinformatic analyses indicate that native G-rich domains from yeast and humans tend to avoid degradation-promoting features, suggesting that the proteostasis network may act as a form of selection at the molecular level that constrains the sequence space accessible to G-rich domains. However, the sensitivity or resistance of G-rich and Q/N-rich domains, respectively, was not always preserved in their native protein contexts, highlighting that proteins can evolve other sequence features to overcome the intrinsic sensitivity of some LCDs to degradation.</abstract><cop>Basel</cop><pub>MDPI AG</pub><pmid>34445649</pmid><doi>10.3390/ijms22168944</doi><orcidid>https://orcid.org/0000-0002-6473-9977</orcidid><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1422-0067 |
ispartof | International journal of molecular sciences, 2021-08, Vol.22 (16), p.8944 |
issn | 1422-0067 1661-6596 1422-0067 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8396281 |
source | Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; MDPI - Multidisciplinary Digital Publishing Institute; PubMed Central |
subjects | Amino acids Asparagine Biodegradation Domains Glutamine Glycine Hydrophobicity Libraries Mutagenesis Proteasomes Protein interaction Proteins Proteomes Sensitivity Ubiquitin Yeast |
title | Generalizable Compositional Features Influencing the Proteostatic Fates of Polar Low-Complexity Domains |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-15T18%3A45%3A59IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Generalizable%20Compositional%20Features%20Influencing%20the%20Proteostatic%20Fates%20of%20Polar%20Low-Complexity%20Domains&rft.jtitle=International%20journal%20of%20molecular%20sciences&rft.au=Cascarina,%20Sean%20M.&rft.date=2021-08-19&rft.volume=22&rft.issue=16&rft.spage=8944&rft.pages=8944-&rft.issn=1422-0067&rft.eissn=1422-0067&rft_id=info:doi/10.3390/ijms22168944&rft_dat=%3Cproquest_pubme%3E2566042908%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2624242042&rft_id=info:pmid/34445649&rfr_iscdi=true |