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Article ; Online: The role of the HORMA domain proteins ATG13 and ATG101 in initiating autophagosome biogenesis

Nguyẽ̂n, Anh / Faesen, Alex C.

FEBS Letters. 2024 Jan., v. 598, no. 1 p.114-126

2024

Abstract: Autophagy is a process of regulated degradation. It eliminates damaged and unnecessary cellular components by engulfing them with a de novo‐generated organelle: the double‐membrane autophagosome. The past three decades have provided us with a detailed ... ...

Abstract	Autophagy is a process of regulated degradation. It eliminates damaged and unnecessary cellular components by engulfing them with a de novo‐generated organelle: the double‐membrane autophagosome. The past three decades have provided us with a detailed parts list of the autophagy initiation machinery, have developed important insights into how these processes function and have identified regulatory proteins. It is now clear that autophagosome biogenesis requires the timely assembly of a complex machinery. However, it is unclear how a putative stable machine is assembled and disassembled and how the different parts cooperate to perform its overall function. Although they have long been somewhat enigmatic in their precise role, HORMA domain proteins (first identified in Hop1p, Rev7p and MAD2 proteins) autophagy‐related protein 13 (ATG13) and ATG101 of the ULK‐kinase complex have emerged as important coordinators of the autophagy‐initiating subcomplexes. Here, we will particularly focus on ATG13 and ATG101 and the role of their unusual metamorphosis in initiating autophagosome biogenesis. We will also explore how this metamorphosis could potentially be purposefully rate‐limiting and speculate on how it could regulate the spontaneous self‐assembly of the autophagy‐initiating machinery.
Keywords	autophagosomes ; autophagy ; biogenesis ; metamorphosis
Language	English
Dates of publication	2024-01
Size	p. 114-126.
Publishing place	John Wiley & Sons, Ltd
Document type	Article ; Online
Note	REVIEW
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.14717
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Shieldin complex assembly kinetics and DNA binding by SHLD3.

Susvirkar, Vivek / Faesen, Alex C

Communications biology

2023 Volume 6, Issue 1, Page(s) 384

Abstract: The Shieldin complex represses end resection at DNA double-strand breaks (DSBs) and thereby serves as a pro-non homologous end joining (NHEJ) factor. The molecular details of the assembly of Shieldin and its recruitment to DSBs are unclear. Shieldin ... ...

Abstract	The Shieldin complex represses end resection at DNA double-strand breaks (DSBs) and thereby serves as a pro-non homologous end joining (NHEJ) factor. The molecular details of the assembly of Shieldin and its recruitment to DSBs are unclear. Shieldin contains two REV7 molecules, which have the rare ability to slowly switch between multiple distinct native states and thereby could dynamically control the assembly of Shieldin. Here, we report the identification of a promiscuous DNA binding domain in SHLD3. At the N-terminus, SHLD3 interacts with a dimer of REV7 molecules. We show that the interaction between SHLD3 and the first REV7 is remarkably slow, while in contrast the interaction between SHLD3 and SHLD2 with a second REV7 molecule is fast and does not require structural remodeling. Overall, these results provide insights into the rate-limiting step of the molecular assembly of the Shieldin complex and its recruitment at DNA DSBs.
MeSH term(s)	Mad2 Proteins/chemistry ; Mad2 Proteins/genetics ; Mad2 Proteins/metabolism ; Cell Cycle Proteins/metabolism ; DNA End-Joining Repair ; DNA Breaks, Double-Stranded ; DNA/genetics ; DNA/metabolism
Chemical Substances	Mad2 Proteins ; Cell Cycle Proteins ; DNA (9007-49-2)
Language	English
Publishing date	2023-04-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2399-3642
ISSN (online)	2399-3642
DOI	10.1038/s42003-023-04757-7
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Article ; Online: The role of the HORMA domain proteins ATG13 and ATG101 in initiating autophagosome biogenesis.

Nguyen, Anh / Faesen, Alex C

FEBS letters

2023 Volume 598, Issue 1, Page(s) 114–126

Abstract: Autophagy is a process of regulated degradation. It eliminates damaged and unnecessary cellular components by engulfing them with a de novo-generated organelle: the double-membrane autophagosome. The past three decades have provided us with a detailed ... ...

Abstract	Autophagy is a process of regulated degradation. It eliminates damaged and unnecessary cellular components by engulfing them with a de novo-generated organelle: the double-membrane autophagosome. The past three decades have provided us with a detailed parts list of the autophagy initiation machinery, have developed important insights into how these processes function and have identified regulatory proteins. It is now clear that autophagosome biogenesis requires the timely assembly of a complex machinery. However, it is unclear how a putative stable machine is assembled and disassembled and how the different parts cooperate to perform its overall function. Although they have long been somewhat enigmatic in their precise role, HORMA domain proteins (first identified in Hop1p, Rev7p and MAD2 proteins) autophagy-related protein 13 (ATG13) and ATG101 of the ULK-kinase complex have emerged as important coordinators of the autophagy-initiating subcomplexes. Here, we will particularly focus on ATG13 and ATG101 and the role of their unusual metamorphosis in initiating autophagosome biogenesis. We will also explore how this metamorphosis could potentially be purposefully rate-limiting and speculate on how it could regulate the spontaneous self-assembly of the autophagy-initiating machinery.
MeSH term(s)	Autophagy-Related Proteins/genetics ; Autophagosomes ; Autophagy/physiology ; Mad2 Proteins
Chemical Substances	Autophagy-Related Proteins ; Mad2 Proteins
Language	English
Publishing date	2023-08-20
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.14717
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Article ; Online: Metamorphosis by ATG13 and ATG101 in human autophagy initiation.

Patel, Anoshi / Faesen, Alex C

Autophagy

2023 Volume 20, Issue 4, Page(s) 968–969

Abstract: Abbreviations: ATG, Autophagy-related, HORMA, protein domain named after HOP1-MAD2-REV7; RB1CC1, RB1 inducible coiled-coil 1; ULK, Unc-51-like kinase. ...

Abstract	Abbreviations: ATG, Autophagy-related, HORMA, protein domain named after HOP1-MAD2-REV7; RB1CC1, RB1 inducible coiled-coil 1; ULK, Unc-51-like kinase.
MeSH term(s)	Humans ; Autophagy/physiology ; Autophagy-Related Proteins/metabolism ; Adaptor Proteins, Vesicular Transport/metabolism ; Models, Biological ; Vesicular Transport Proteins
Chemical Substances	Autophagy-Related Proteins ; ATG13 protein, human ; ATG101 protein, human ; Adaptor Proteins, Vesicular Transport ; Vesicular Transport Proteins
Language	English
Publishing date	2023-07-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2454135-7
ISSN	1554-8635 ; 1554-8627
ISSN (online)	1554-8635
ISSN	1554-8627
DOI	10.1080/15548627.2023.2230054
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Article ; Online: The (phospho) needle in the (MELT) Haystack.

Faesen, Alex C / Musacchio, Andrea

Molecular cell

2015 Volume 57, Issue 5, Page(s) 765–766

Abstract: The spindle assembly checkpoint promotes chromosome bi-orientation and halts mitotic progression in the presence of improper kinetochore-microtubule attachments. Knl1, a kinetochore protein, acts as a scaffold for SAC signaling. A new study unveils ... ...

Abstract	The spindle assembly checkpoint promotes chromosome bi-orientation and halts mitotic progression in the presence of improper kinetochore-microtubule attachments. Knl1, a kinetochore protein, acts as a scaffold for SAC signaling. A new study unveils remarkable complexity in the interplay of Knl1 phosphorylation and SAC function (Vleugel et al., 2015).
MeSH term(s)	Cell Cycle Proteins/metabolism ; Humans ; Kinetochores/metabolism ; Microtubule-Associated Proteins/metabolism ; Mitosis ; Poly-ADP-Ribose Binding Proteins ; Protein-Serine-Threonine Kinases/metabolism
Chemical Substances	BUB3 protein, human ; Cell Cycle Proteins ; Knl1 protein, human ; Microtubule-Associated Proteins ; Poly-ADP-Ribose Binding Proteins ; BUB1 protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2015-02-26
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2015.02.026
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Article ; Online: Metamorphic proteins at the basis of human autophagy initiation and lipid transfer.

Nguyen, Anh / Lugarini, Francesca / David, Céline / Hosnani, Pouya / Alagöz, Çağla / Friedrich, Annabelle / Schlütermann, David / Knotkova, Barbora / Patel, Anoshi / Parfentev, Iwan / Urlaub, Henning / Meinecke, Michael / Stork, Björn / Faesen, Alex C

Molecular cell

2023 Volume 83, Issue 12, Page(s) 2077–2090.e12

Abstract: Autophagy is a conserved intracellular degradation pathway that generates de novo double-membrane autophagosomes to target a wide range of material for lysosomal degradation. In multicellular organisms, autophagy initiation requires the timely assembly ... ...

Abstract	Autophagy is a conserved intracellular degradation pathway that generates de novo double-membrane autophagosomes to target a wide range of material for lysosomal degradation. In multicellular organisms, autophagy initiation requires the timely assembly of a contact site between the ER and the nascent autophagosome. Here, we report the in vitro reconstitution of a full-length seven-subunit human autophagy initiation supercomplex built on a core complex of ATG13-101 and ATG9. Assembly of this core complex requires the rare ability of ATG13 and ATG101 to switch between distinct folds. The slow spontaneous metamorphic conversion is rate limiting for the self-assembly of the supercomplex. The interaction of the core complex with ATG2-WIPI4 enhances tethering of membrane vesicles and accelerates lipid transfer of ATG2 by both ATG9 and ATG13-101. Our work uncovers the molecular basis of the contact site and its assembly mechanisms imposed by the metamorphosis of ATG13-101 to regulate autophagosome biogenesis in space and time.
MeSH term(s)	Humans ; Autophagy-Related Proteins/genetics ; Autophagy-Related Proteins/metabolism ; Autophagy/physiology ; Autophagosomes/metabolism ; Membrane Proteins/metabolism ; Lipids
Chemical Substances	Autophagy-Related Proteins ; Membrane Proteins ; Lipids
Language	English
Publishing date	2023-05-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2023.04.026
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Article ; Online: MAD2L2 dimerization and TRIP13 control shieldin activity in DNA repair.

de Krijger, Inge / Föhr, Bastian / Pérez, Santiago Hernández / Vincendeau, Estelle / Serrat, Judit / Thouin, Alexander Marc / Susvirkar, Vivek / Lescale, Chloé / Paniagua, Inés / Hoekman, Liesbeth / Kaur, Simranjeet / Altelaar, Maarten / Deriano, Ludovic / Faesen, Alex C / Jacobs, Jacqueline J L

Nature communications

2021 Volume 12, Issue 1, Page(s) 5421

Abstract: MAD2L2 (REV7) plays an important role in DNA double-strand break repair. As a member of the shieldin complex, consisting of MAD2L2, SHLD1, SHLD2 and SHLD3, it controls DNA repair pathway choice by counteracting DNA end-resection. Here we investigated the ...

Abstract	MAD2L2 (REV7) plays an important role in DNA double-strand break repair. As a member of the shieldin complex, consisting of MAD2L2, SHLD1, SHLD2 and SHLD3, it controls DNA repair pathway choice by counteracting DNA end-resection. Here we investigated the requirements for shieldin complex assembly and activity. Besides a dimerization-surface, HORMA-domain protein MAD2L2 has the extraordinary ability to wrap its C-terminus around SHLD3, likely creating a very stable complex. We show that appropriate function of MAD2L2 within shieldin requires its dimerization, mediated by SHLD2 and accelerating MAD2L2-SHLD3 interaction. Dimerization-defective MAD2L2 impairs shieldin assembly and fails to promote NHEJ. Moreover, MAD2L2 dimerization, along with the presence of SHLD3, allows shieldin to interact with the TRIP13 ATPase, known to drive topological switches in HORMA-domain proteins. We find that appropriate levels of TRIP13 are important for proper shieldin (dis)assembly and activity in DNA repair. Together our data provide important insights in the dependencies for shieldin activity.
MeSH term(s)	ATPases Associated with Diverse Cellular Activities/chemistry ; ATPases Associated with Diverse Cellular Activities/genetics ; ATPases Associated with Diverse Cellular Activities/metabolism ; Animals ; Binding Sites ; Cell Cycle Proteins/chemistry ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Line ; Cell Line, Tumor ; Cisplatin/pharmacology ; DNA/chemistry ; DNA/genetics ; DNA/metabolism ; DNA Breaks, Double-Stranded ; DNA Repair ; DNA-Binding Proteins/chemistry ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Fibroblasts/cytology ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Gene Expression ; HEK293 Cells ; HeLa Cells ; Humans ; Mad2 Proteins/chemistry ; Mad2 Proteins/genetics ; Mad2 Proteins/metabolism ; Mice ; Phthalazines/pharmacology ; Piperazines/pharmacology ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Multimerization ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism
Chemical Substances	Cell Cycle Proteins ; DNA-Binding Proteins ; MAD2L2 protein, human ; Mad2 Proteins ; Phthalazines ; Piperazines ; Recombinant Proteins ; SHLD1 protein, human ; SHLD2 protein, human ; SHLD3 protein, human ; DNA (9007-49-2) ; ATPases Associated with Diverse Cellular Activities (EC 3.6.4.-) ; TRIP13 protein, human (EC 3.6.4.-) ; Cisplatin (Q20Q21Q62J) ; olaparib (WOH1JD9AR8)
Language	English
Publishing date	2021-09-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-25724-y
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Article ; Online: BubR1 Promotes Bub3-Dependent APC/C Inhibition during Spindle Assembly Checkpoint Signaling.

Overlack, Katharina / Bange, Tanja / Weissmann, Florian / Faesen, Alex C / Maffini, Stefano / Primorac, Ivana / Müller, Franziska / Peters, Jan-Michael / Musacchio, Andrea

Current biology : CB

2017 Volume 27, Issue 19, Page(s) 2915–2927.e7

Abstract: The spindle assembly checkpoint (SAC) prevents premature sister chromatid separation during mitosis. Phosphorylation of unattached kinetochores by the Mps1 kinase promotes recruitment of SAC machinery that catalyzes assembly of the SAC effector mitotic ... ...

Abstract	The spindle assembly checkpoint (SAC) prevents premature sister chromatid separation during mitosis. Phosphorylation of unattached kinetochores by the Mps1 kinase promotes recruitment of SAC machinery that catalyzes assembly of the SAC effector mitotic checkpoint complex (MCC). The SAC protein Bub3 is a phospho-amino acid adaptor that forms structurally related stable complexes with functionally distinct paralogs named Bub1 and BubR1. A short motif ("loop") of Bub1, but not the equivalent loop of BubR1, enhances binding of Bub3 to kinetochore phospho-targets. Here, we asked whether the BubR1 loop directs Bub3 to different phospho-targets. The BubR1 loop is essential for SAC function and cannot be removed or replaced with the Bub1 loop. BubR1 loop mutants bind Bub3 and are normally incorporated in MCC in vitro but have reduced ability to inhibit the MCC target anaphase-promoting complex (APC/C), suggesting that BubR1:Bub3 recognition and inhibition of APC/C requires phosphorylation. Thus, small sequence differences in Bub1 and BubR1 direct Bub3 to different phosphorylated targets in the SAC signaling cascade.
MeSH term(s)	Anaphase-Promoting Complex-Cyclosome/antagonists & inhibitors ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Humans ; M Phase Cell Cycle Checkpoints/physiology ; Phosphorylation ; Poly-ADP-Ribose Binding Proteins/genetics ; Poly-ADP-Ribose Binding Proteins/metabolism ; Protein-Serine-Threonine Kinases/genetics ; Protein-Serine-Threonine Kinases/metabolism ; Signal Transduction ; Spindle Apparatus/metabolism
Chemical Substances	BUB3 protein, human ; Cell Cycle Proteins ; Poly-ADP-Ribose Binding Proteins ; Anaphase-Promoting Complex-Cyclosome (EC 2.3.2.27) ; BUB1 protein, human (EC 2.7.11.1) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2017-10-09
Publishing country	England
Document type	Journal Article
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2017.08.033
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Article ; Online: Basis of catalytic assembly of the mitotic checkpoint complex.

Faesen, Alex C / Thanasoula, Maria / Maffini, Stefano / Breit, Claudia / Müller, Franziska / van Gerwen, Suzan / Bange, Tanja / Musacchio, Andrea

Nature

2017 Volume 542, Issue 7642, Page(s) 498–502

Abstract: In mitosis, for each daughter cell to inherit an accurate copy of the genome from the mother cell, sister chromatids in the mother cell must attach to microtubules emanating from opposite poles of the mitotic spindle, a process known as bi-orientation. A ...

Abstract	In mitosis, for each daughter cell to inherit an accurate copy of the genome from the mother cell, sister chromatids in the mother cell must attach to microtubules emanating from opposite poles of the mitotic spindle, a process known as bi-orientation. A surveillance mechanism, termed the spindle assembly checkpoint (SAC), monitors the microtubule attachment process and can temporarily halt the separation of sister chromatids and the completion of mitosis until bi-orientation is complete. SAC failure results in abnormal chromosome numbers, termed aneuploidy, in the daughter cells, a hallmark of many tumours. The HORMA-domain-containing protein mitotic arrest deficient 2 (MAD2) is a subunit of the SAC effector mitotic checkpoint complex (MCC). Structural conversion from the open to the closed conformation of MAD2 is required for MAD2 to be incorporated into the MCC. In vitro, MAD2 conversion and MCC assembly take several hours, but in cells the SAC response is established in a few minutes. Here, to address this discrepancy, we reconstituted a near-complete SAC signalling system with purified components and monitored assembly of the MCC in real time. A marked acceleration in MAD2 conversion and MCC assembly was observed when monopolar spindle 1 (MPS1) kinase phosphorylated the MAD1-MAD2 complex, triggering it to act as the template for MAD2 conversion and therefore contributing to the establishment of a physical platform for MCC assembly. Thus, catalytic activation of the SAC depends on regulated protein-protein interactions that accelerate the spontaneous but rate-limiting conversion of MAD2 required for MCC assembly.
MeSH term(s)	Biocatalysis ; Cell Cycle Proteins/metabolism ; Humans ; Kinetics ; Kinetochores/metabolism ; M Phase Cell Cycle Checkpoints/physiology ; Mad2 Proteins/metabolism ; Multiprotein Complexes/chemistry ; Multiprotein Complexes/metabolism ; Nuclear Proteins/metabolism ; Phosphorylation ; Protein Binding ; Protein Serine-Threonine Kinases/metabolism ; Protein Stability ; Protein-Tyrosine Kinases/metabolism ; Spindle Apparatus/metabolism ; Time Factors
Chemical Substances	Cell Cycle Proteins ; MAD1L1 protein, human ; MAD2L1 protein, human ; Mad2 Proteins ; Multiprotein Complexes ; Nuclear Proteins ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; TTK protein, human (EC 2.7.12.1)
Language	English
Publishing date	2017-01-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature21384
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Article ; Online: The role of UBL domains in ubiquitin-specific proteases.

Faesen, Alex C / Luna-Vargas, Mark P A / Sixma, Titia K

Biochemical Society transactions

2012 Volume 40, Issue 3, Page(s) 539–545

Abstract: Ubiquitin conjugation and deconjugation provides a powerful signalling system to change the fate of its target enzymes. Ubiquitination levels are organized through a balance between ubiquitinating E1, E2 and E3 enzymes and deubiquitination by DUBs ( ... ...

Abstract	Ubiquitin conjugation and deconjugation provides a powerful signalling system to change the fate of its target enzymes. Ubiquitination levels are organized through a balance between ubiquitinating E1, E2 and E3 enzymes and deubiquitination by DUBs (deubiquitinating enzymes). These enzymes are tightly regulated to control their activity. In the present article, we discuss the different ways in which DUBs of the USP (ubiquitin-specific protease) family are regulated by internal domains with a UBL (ubiquitin-like) fold. The UBL domain in USP14 is important for its localization at the proteasome, which enhances catalysis. In contrast, a UBL domain in USP4 binds to the catalytic domain and competes with ubiquitin binding. In this process, the UBL domain mimics ubiquitin and partially inhibits catalysis. In USP7, there are five consecutive UBL domains, of which the last two affect catalytic activity. Surprisingly, they do not act like ubiquitin and activate catalysis rather than inhibiting it. These C-terminal UBL domains promote a conformational change that allows ubiquitin binding and organizes the catalytic centre. Thus it seems that UBL domains have different functions in different USPs. Other proteins can modulate the roles of UBL domains in USP4 and USP7. On one hand, the inhibition of USP4 can be relieved when the UBL is sequestered by another USP. On the other, the activation of USP7 is increased, when the UBL-activated state is stabilized by allosteric binding of GMP synthetase. Altogether, UBL domains appear to be able to regulate catalytic activity in USPs, but they can use widely different mechanisms of action, in which they may, as in USP4, or may not, as in USP7, use the direct resemblance to ubiquitin.
MeSH term(s)	Animals ; Biocatalysis ; Endopeptidases/chemistry ; Endopeptidases/metabolism ; Humans ; Models, Molecular ; Proteasome Endopeptidase Complex/metabolism ; Protein Structure, Tertiary ; Structure-Activity Relationship ; Ubiquitin-Specific Proteases
Chemical Substances	Endopeptidases (EC 3.4.-) ; Ubiquitin-Specific Proteases (EC 3.4.19.12) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2012-06-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20120004
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