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Article ; Online: Profiling CELMoD-Mediated Degradation of Cereblon Neosubstrates.

Thompson, Joel W / Clayton, Thomas / Khambatta, Gody / Bateman, Leslie A / Carroll, Christopher W / Chamberlain, Philip P / Matyskiela, Mary E

Methods in molecular biology (Clifton, N.J.)

2021 Volume 2365, Page(s) 283–300

Abstract: Targeted protein degradation is garnering increased attention as a therapeutic modality due in part to its promise of modulating targets previously considered undruggable. Cereblon E3 Ligase Modulating Drugs (CELMoDs) are one of the most well- ... ...

Abstract	Targeted protein degradation is garnering increased attention as a therapeutic modality due in part to its promise of modulating targets previously considered undruggable. Cereblon E3 Ligase Modulating Drugs (CELMoDs) are one of the most well-characterized therapeutics employing this modality. CELMoDs hijack Cereblon E3 ligase activity causing neosubstrates to be ubiquitinated and degraded in the proteasome. Here, we describe a suite of assays-cellular substrate degradation, confirmation of CELMoD mechanism of action, in vitro ubiquitination, and Cereblon binding-that can be used to characterize CELMoD-mediated degradation of Cereblon neosubstrates. While the assays presented herein can be run independently, when combined they provide a strong platform to support the discovery and optimization of CELMoDs and fuel validation of targets degraded by this drug modality.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Nanostructures ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
Chemical Substances	Adaptor Proteins, Signal Transducing ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2021-08-25
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-1665-9_15
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Molecular glue CELMoD compounds are regulators of cereblon conformation.

Watson, Edmond R / Novick, Scott / Matyskiela, Mary E / Chamberlain, Philip P / H de la Peña, Andres / Zhu, Jinyi / Tran, Eileen / Griffin, Patrick R / Wertz, Ingrid E / Lander, Gabriel C

Science (New York, N.Y.)

2022 Volume 378, Issue 6619, Page(s) 549–553

Abstract: Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior crystallographic studies defined the drug-binding site ... ...

Abstract	Cereblon (CRBN) is a ubiquitin ligase (E3) substrate receptor protein co-opted by CRBN E3 ligase modulatory drug (CELMoD) agents that target therapeutically relevant proteins for degradation. Prior crystallographic studies defined the drug-binding site within CRBN's thalidomide-binding domain (TBD), but the allostery of drug-induced neosubstrate binding remains unclear. We performed cryo-electron microscopy analyses of the DNA damage-binding protein 1 (DDB1)-CRBN apo complex and compared these structures with DDB1-CRBN in the presence of CELMoD compounds alone and complexed with neosubstrates. Association of CELMoD compounds to the TBD is necessary and sufficient for triggering CRBN allosteric rearrangement from an open conformation to the canonical closed conformation. The neosubstrate Ikaros only stably associates with the closed CRBN conformation, illustrating the importance of allostery for CELMoD compound efficacy and informing structure-guided design strategies to improve therapeutic efficacy.
MeSH term(s)	Adaptor Proteins, Signal Transducing/chemistry ; Cryoelectron Microscopy ; Thalidomide/chemistry ; Ubiquitin-Protein Ligases/chemistry ; Protein Domains ; Allosteric Regulation
Chemical Substances	Adaptor Proteins, Signal Transducing ; CRBN protein, human ; Thalidomide (4Z8R6ORS6L) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2022-11-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.add7574
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Article ; Online: Design principles of a universal protein degradation machine.

Matyskiela, Mary E / Martin, Andreas

Journal of molecular biology

2012 Volume 425, Issue 2, Page(s) 199–213

Abstract: The 26S proteasome is a 2.5-MDa, 32-subunit ATP-dependent protease that is responsible for the degradation of ubiquitinated protein targets in all eukaryotic cells. This proteolytic machine consists of a barrel-shaped peptidase capped by a large ... ...

Abstract	The 26S proteasome is a 2.5-MDa, 32-subunit ATP-dependent protease that is responsible for the degradation of ubiquitinated protein targets in all eukaryotic cells. This proteolytic machine consists of a barrel-shaped peptidase capped by a large regulatory particle, which contains a heterohexameric AAA+ unfoldase as well as several structural modules of previously unknown function. Recent electron microscopy (EM) studies have allowed major breakthroughs in understanding the architecture of the regulatory particle, revealing that the additional modules provide a structural framework to position critical, ubiquitin-interacting subunits and thus allow the 26S proteasome to function as a universal degradation machine for a wide variety of protein substrates. The EM studies have also uncovered surprising asymmetries in the spatial arrangement of proteasome subunits, yet the functional significance of these architectural features remains unclear. This review will summarize the recent findings on 26S proteasome structure and discuss the mechanistic implications for substrate binding, deubiquitination, unfolding, and degradation.
MeSH term(s)	Animals ; Humans ; Proteasome Endopeptidase Complex/metabolism ; Protein Processing, Post-Translational ; Proteins/metabolism ; Proteolysis ; Ubiquitin/metabolism
Chemical Substances	Proteins ; Ubiquitin ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; ATP dependent 26S protease (EC 3.4.99.-)
Language	English
Publishing date	2012-11-09
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2012.11.001
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Article: Design Principles of a Universal Protein Degradation Machine

Matyskiela, Mary E / Martin, Andreas

Journal of molecular biology. 2013 Jan. 23, v. 425, no. 2

2013

Abstract	The 26S proteasome is a 2.5-MDa, 32-subunit ATP-dependent protease that is responsible for the degradation of ubiquitinated protein targets in all eukaryotic cells. This proteolytic machine consists of a barrel-shaped peptidase capped by a large regulatory particle, which contains a heterohexameric AAA+ unfoldase as well as several structural modules of previously unknown function. Recent electron microscopy (EM) studies have allowed major breakthroughs in understanding the architecture of the regulatory particle, revealing that the additional modules provide a structural framework to position critical, ubiquitin-interacting subunits and thus allow the 26S proteasome to function as a universal degradation machine for a wide variety of protein substrates. The EM studies have also uncovered surprising asymmetries in the spatial arrangement of proteasome subunits, yet the functional significance of these architectural features remains unclear. This review will summarize the recent findings on 26S proteasome structure and discuss the mechanistic implications for substrate binding, deubiquitination, unfolding, and degradation.
Keywords	electron microscopy ; eukaryotic cells ; proteasome endopeptidase complex ; protein degradation ; proteinases ; proteolysis
Language	English
Dates of publication	2013-0123
Size	p. 199-213.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2012.11.001
Database	NAL-Catalogue (AGRICOLA)

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Thesis ; Online: Substrate binding by the anaphase-promoting complex

Matyskiela, Mary E.

2009

Abstract: The anaphase-promoting complex or cyclosome (APC/C) is a ubiquitin ligase essential for the completion of mitosis in all eukaryotic cells. Substrates are recruited to the APC/C by activator proteins (Cdc20 or Cdh1), but it is not known where substrates ... ...

Abstract	The anaphase-promoting complex or cyclosome (APC/C) is a ubiquitin ligase essential for the completion of mitosis in all eukaryotic cells. Substrates are recruited to the APC/C by activator proteins (Cdc20 or Cdh1), but it is not known where substrates are bound during catalysis. We explored this problem by analyzing mutations in the tetratricopeptide repeat (TPR)-containing APC/C subunits. We identified residues in Cdc23 and Cdc27 that are required for APC/C binding to Cdc20 and Cdh1 and for APC/C function in vivo. Mutation of these sites increased the rate of activator dissociation from the APC/C but did not affect reaction processivity, suggesting that the mutations have little effect on substrate dissociation from the active site. Further studies revealed that activator dissociation from the APC/C is inhibited by substrate, and that substrates are not bound solely to activator during catalysis but interact bivalently with an additional binding site on the APC/C core.
Keywords	Molecular biology\|Biochemistry
Subject code	572
Language	ENG
Publishing date	2009-01-01 00:00:01.0
Publisher	University of California, San Francisco
Publishing country	us
Document type	Thesis ; Online
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Article ; Online: Specific lid-base contacts in the 26s proteasome control the conformational switching required for substrate degradation.

Greene, Eric R / Goodall, Ellen A / de la Peña, Andres H / Matyskiela, Mary E / Lander, Gabriel C / Martin, Andreas

eLife

2019 Volume 8

Abstract: The 26S proteasome is essential for proteostasis and the regulation of vital processes through ATP-dependent degradation of ubiquitinated substrates. To accomplish the multi-step degradation process, the proteasome's regulatory particle, consisting of ... ...

Abstract	The 26S proteasome is essential for proteostasis and the regulation of vital processes through ATP-dependent degradation of ubiquitinated substrates. To accomplish the multi-step degradation process, the proteasome's regulatory particle, consisting of lid and base subcomplexes, undergoes major conformational changes whose origin is unknown. Investigating the
MeSH term(s)	Adenosine Triphosphatases/chemistry ; Adenosine Triphosphatases/metabolism ; Endosomal Sorting Complexes Required for Transport/metabolism ; Models, Molecular ; Nucleotides/metabolism ; Proteasome Endopeptidase Complex/chemistry ; Proteasome Endopeptidase Complex/metabolism ; Protein Conformation ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligase Complexes/metabolism
Chemical Substances	Endosomal Sorting Complexes Required for Transport ; Nucleotides ; Rpn5 protein, S cerevisiae ; Saccharomyces cerevisiae Proteins ; Ubiquitin ; Ubiquitin-Protein Ligase Complexes (EC 2.3.2.23) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; ATP dependent 26S protease (EC 3.4.99.-) ; Adenosine Triphosphatases (EC 3.6.1.-) ; RPT6 protein, S cerevisiae (EC 3.6.1.3) ; RSP5 protein, S cerevisiae (EC 6.3.2.-)
Language	English
Publishing date	2019-11-28
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.49806
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Article ; Online: Conformational switching of the 26S proteasome enables substrate degradation.

Matyskiela, Mary E / Lander, Gabriel C / Martin, Andreas

Nature structural & molecular biology

2013 Volume 20, Issue 7, Page(s) 781–788

Abstract: The 26S proteasome is the major eukaryotic ATP-dependent protease, responsible for regulating the proteome through degradation of ubiquitin-tagged substrates. Its regulatory particle, containing the heterohexameric AAA+ ATPase motor and the essential ... ...

Abstract	The 26S proteasome is the major eukaryotic ATP-dependent protease, responsible for regulating the proteome through degradation of ubiquitin-tagged substrates. Its regulatory particle, containing the heterohexameric AAA+ ATPase motor and the essential deubiquitinase Rpn11, recognizes substrates, removes their ubiquitin chains and translocates them into the associated peptidase after unfolding, but detailed mechanisms remain unknown. Here we present the 26S proteasome structure from Saccharomyces cerevisiae during substrate degradation, showing that the regulatory particle switches from a preengaged to a translocation-competent conformation. This conformation is characterized by a rearranged ATPase ring with uniform subunit interfaces, a widened central channel coaxially aligned with the peptidase and a spiral orientation of pore loops that suggests a rapid progression of ATP-hydrolysis events around the ring. Notably, Rpn11 moves from an occluded position to directly above the central pore, thus facilitating substrate deubiquitination concomitant with translocation.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Catalytic Domain ; Cryoelectron Microscopy ; Endopeptidases/metabolism ; Models, Molecular ; Mutagenesis, Site-Directed ; Proteasome Endopeptidase Complex/chemistry ; Proteasome Endopeptidase Complex/genetics ; Proteasome Endopeptidase Complex/metabolism ; Proteasome Endopeptidase Complex/ultrastructure ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary ; Proteolysis ; Saccharomyces cerevisiae/enzymology ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/chemistry ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Saccharomyces cerevisiae Proteins/ultrastructure ; Structure-Activity Relationship ; Substrate Specificity ; Ubiquitinated Proteins/metabolism
Chemical Substances	RPN11 protein, S cerevisiae ; Saccharomyces cerevisiae Proteins ; Ubiquitinated Proteins ; Adenosine Triphosphate (8L70Q75FXE) ; Endopeptidases (EC 3.4.-) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; ATP dependent 26S protease (EC 3.4.99.-)
Language	English
Publishing date	2013-06-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/nsmb.2616
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Article ; Online: Analysis of activator-binding sites on the APC/C supports a cooperative substrate-binding mechanism.

Matyskiela, Mary E / Morgan, David O

Molecular cell

2009 Volume 34, Issue 1, Page(s) 68–80

Abstract	The anaphase-promoting complex or cyclosome (APC/C) is a ubiquitin ligase essential for the completion of mitosis in all eukaryotic cells. Substrates are recruited to the APC/C by activator proteins (Cdc20 or Cdh1), but it is not known where substrates are bound during catalysis. We explored this problem by analyzing mutations in the tetratricopeptide-repeat-containing APC/C subunits. We identified residues in Cdc23 and Cdc27 that are required for APC/C binding to Cdc20 and Cdh1 and for APC/C function in vivo. Mutation of these sites increased the rate of activator dissociation from the APC/C but did not affect reaction processivity, suggesting that the mutations have little effect on substrate dissociation from the active site. Further studies revealed that activator dissociation from the APC/C is inhibited by substrate, and that substrates are not bound solely to activator during catalysis but interact bivalently with an additional binding site on the APC/C core.
MeSH term(s)	Amino Acid Motifs ; Amino Acid Sequence ; Anaphase-Promoting Complex-Cyclosome ; Apc8 Subunit, Anaphase-Promoting Complex-Cyclosome ; Binding Sites ; Cdc20 Proteins ; Cdh1 Proteins ; Cell Cycle Proteins/chemistry ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Enzyme Activation ; Models, Biological ; Molecular Sequence Data ; Mutation ; Protein Binding/physiology ; Saccharomyces cerevisiae/enzymology ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/chemistry ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Sequence Analysis, Protein ; Ubiquitin-Protein Ligase Complexes/chemistry ; Ubiquitin-Protein Ligase Complexes/metabolism
Chemical Substances	Apc8 Subunit, Anaphase-Promoting Complex-Cyclosome ; CDC20 protein, S cerevisiae ; CDC23 protein, S cerevisiae ; CDH1 protein, S cerevisiae ; Cdc20 Proteins ; Cdh1 Proteins ; Cell Cycle Proteins ; Saccharomyces cerevisiae Proteins ; Ubiquitin-Protein Ligase Complexes (EC 2.3.2.23) ; Anaphase-Promoting Complex-Cyclosome (EC 2.3.2.27)
Language	English
Publishing date	2009-04-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2009.02.027
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Article ; Online: Crystal structure of the SALL4-pomalidomide-cereblon-DDB1 complex.

Matyskiela, Mary E / Clayton, Thomas / Zheng, Xinde / Mayne, Christopher / Tran, Eileen / Carpenter, Aaron / Pagarigan, Barbra / McDonald, Joseph / Rolfe, Mark / Hamann, Lawrence G / Lu, Gang / Chamberlain, Philip P

Nature structural & molecular biology

2020 Volume 27, Issue 4, Page(s) 319–322

Abstract: Thalidomide-dependent degradation of the embryonic transcription factor SALL4 by the ... ...

Abstract	Thalidomide-dependent degradation of the embryonic transcription factor SALL4 by the CRL4
MeSH term(s)	Adaptor Proteins, Signal Transducing/chemistry ; Adaptor Proteins, Signal Transducing/genetics ; Crystallography, X-Ray ; DNA-Binding Proteins/chemistry ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/ultrastructure ; Humans ; Multiprotein Complexes/chemistry ; Multiprotein Complexes/genetics ; Multiprotein Complexes/ultrastructure ; Protein Binding ; Protein Conformation ; Proteolysis/drug effects ; Substrate Specificity ; Thalidomide/analogs & derivatives ; Thalidomide/chemistry ; Thalidomide/pharmacology ; Transcription Factors/chemistry ; Transcription Factors/genetics ; Transcription Factors/ultrastructure ; Ubiquitin-Protein Ligases/chemistry ; Ubiquitin-Protein Ligases/ultrastructure ; Ubiquitination/genetics
Chemical Substances	Adaptor Proteins, Signal Transducing ; CRBN protein, human ; DDB1 protein, human ; DNA-Binding Proteins ; Multiprotein Complexes ; SALL4 protein, human ; Transcription Factors ; Thalidomide (4Z8R6ORS6L) ; pomalidomide (D2UX06XLB5) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2020-04-06
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/s41594-020-0405-9
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Article ; Online: Cereblon Modulators Target ZBTB16 and Its Oncogenic Fusion Partners for Degradation via Distinct Structural Degrons.

Matyskiela, Mary E / Zhu, Jinyi / Baughman, Joshua M / Clayton, Thomas / Slade, Michelle / Wong, Hon Kit / Danga, Kristina / Zheng, Xinde / Labow, Mark / LeBrun, Laurie / Lu, Gang / Chamberlain, Philip P / Thompson, Joel W

ACS chemical biology

2020 Volume 15, Issue 12, Page(s) 3149–3158

Abstract: There is a growing interest in using targeted protein degradation as a therapeutic modality in view of its potential to expand the druggable proteome. One avenue to using this modality is via molecular glue based Cereblon E3 Ligase Modulating Drug ... ...

Abstract	There is a growing interest in using targeted protein degradation as a therapeutic modality in view of its potential to expand the druggable proteome. One avenue to using this modality is via molecular glue based Cereblon E3 Ligase Modulating Drug compounds. Here, we report the identification of the transcription factor ZBTB16 as a Cereblon neosubstrate. We also report two new Cereblon modulators, CC-3060 and CC-647, that promote ZBTB16 degradation. Unexpectedly, CC-3060 and CC-647 target ZBTB16 for degradation by primarily engaging distinct structural degrons on different zinc finger domains. The reciprocal fusion proteins, ZBTB16-RARα and RARα-ZBTB16, which cause a rare acute promyelocytic leukemia, contain these same structural degrons and can be targeted for proteasomal degradation with Cereblon modulator treatment. Thus, a targeted protein degradation approach via Cereblon modulators may represent a novel therapeutic strategy in acute promyelocytic leukemia where
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Humans ; Leukemia, Promyelocytic, Acute/metabolism ; Oncogene Proteins, Fusion/metabolism ; Promyelocytic Leukemia Zinc Finger Protein/drug effects ; Proteolysis ; Retinoic Acid Receptor alpha/metabolism ; Substrate Specificity ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; CRBN protein, human ; Oncogene Proteins, Fusion ; Promyelocytic Leukemia Zinc Finger Protein ; Retinoic Acid Receptor alpha ; ZBTB16 protein, human (147855-37-6) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2020-11-18
Publishing country	United States
Document type	Journal Article
ISSN	1554-8937
ISSN (online)	1554-8937
DOI	10.1021/acschembio.0c00674
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