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Article ; Online: The O-GlcNAc cycling in neurodevelopment and associated diseases.

Wenzel, Dawn M / Olivier-Van Stichelen, Stephanie

2022 Volume 50, Issue 6, Page(s) 1693–1702

Abstract: Proper neuronal development is essential to growth and adult brain function. Alterations at any step of this highly organized sequence of events, due to genetic mutations or environmental factors, triggers brain malformations, which are leading causes of ...

Abstract	Proper neuronal development is essential to growth and adult brain function. Alterations at any step of this highly organized sequence of events, due to genetic mutations or environmental factors, triggers brain malformations, which are leading causes of diseases including epilepsy, intellectual disabilities, and many others. The role of glycosylation in neuronal development has been emphasized for many years, notably in studying human congenital disorders of glycosylation (CDGs). These diseases highlight that genetic defects in glycosylation pathways are almost always associated with severe neurological abnormalities, suggesting that glycosylation plays an essential role in early brain development. Congenital disorders of O-GlcNAcylation are no exception, and all mutations of the O-GlcNAc transferase (OGT) are associated with X-linked intellectual disabilities (XLID). In addition, mouse models and in vitro mechanistic studies have reinforced the essential role of O-GlcNAcylation in neuronal development and signaling. In this review, we give an overview of the role of O-GlcNAcylation in this critical physiological process and emphasize the consequences of its dysregulation.
MeSH term(s)	Animals ; Humans ; Mice ; Acetylglucosamine/metabolism ; Glycosylation ; Intellectual Disability/genetics ; Mutation ; N-Acetylglucosaminyltransferases/metabolism ; Protein Processing, Post-Translational ; Signal Transduction
Chemical Substances	Acetylglucosamine (V956696549) ; N-Acetylglucosaminyltransferases (EC 2.4.1.-)
Language	English
Publishing date	2022-11-16
Publishing country	England
Document type	Review ; Journal Article
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST20220539
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Article ; Online: Comprehensive analysis of the human ESCRT-III-MIT domain interactome reveals new cofactors for cytokinetic abscission.

Wenzel, Dawn M / Mackay, Douglas R / Skalicky, Jack J / Paine, Elliott L / Miller, Matthew S / Ullman, Katharine S / Sundquist, Wesley I

eLife

2022 Volume 11

Abstract: The 12 related human ESCRT-III proteins form filaments that constrict membranes and mediate fission, including during cytokinetic abscission. The C-terminal tails of polymerized ESCRT-III subunits also bind proteins that contain Microtubule-Interacting ... ...

Abstract	The 12 related human ESCRT-III proteins form filaments that constrict membranes and mediate fission, including during cytokinetic abscission. The C-terminal tails of polymerized ESCRT-III subunits also bind proteins that contain Microtubule-Interacting and Trafficking (MIT) domains. MIT domains can interact with ESCRT-III tails in many different ways to create a complex binding code that is used to recruit essential cofactors to sites of ESCRT activity. Here, we have comprehensively and quantitatively mapped the interactions between all known ESCRT-III tails and 19 recombinant human MIT domains. We measured 228 pairwise interactions, quantified 60 positive interactions, and discovered 18 previously unreported interactions. We also report the crystal structure of the SPASTIN MIT domain in complex with the IST1 C-terminal tail. Three MIT enzymes were studied in detail and shown to: (1) localize to cytokinetic midbody membrane bridges through interactions with their specific ESCRT-III binding partners (SPASTIN-IST1, KATNA1-CHMP3, and CAPN7-IST1), (2) function in abscission (SPASTIN, KATNA1, and CAPN7), and (3) function in the 'NoCut' abscission checkpoint (SPASTIN and CAPN7). Our studies define the human MIT-ESCRT-III interactome, identify new factors and activities required for cytokinetic abscission and its regulation, and provide a platform for analyzing ESCRT-III and MIT cofactor interactions in all ESCRT-mediated processes.
MeSH term(s)	Cytokinesis/physiology ; Endosomal Sorting Complexes Required for Transport/metabolism ; Humans ; Microtubules/metabolism ; Spastin/metabolism
Chemical Substances	CHMP3 protein, human ; Endosomal Sorting Complexes Required for Transport ; Spastin (EC 3.6.4.3)
Language	English
Publishing date	2022-09-15
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.77779
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Article ; Online: Following Ariadne's thread: a new perspective on RBR ubiquitin ligases.

Wenzel, Dawn M / Klevit, Rachel E

BMC biology

2012 Volume 10, Page(s) 24

Abstract: Ubiquitin signaling pathways rely on E3 ligases for effecting the final transfer of ubiquitin from E2 ubiquitin conjugating enzymes to a protein target. Here we re-evaluate the hybrid RING/HECT mechanism used by the E3 family RING-between-RINGs (RBRs) to ...

Abstract	Ubiquitin signaling pathways rely on E3 ligases for effecting the final transfer of ubiquitin from E2 ubiquitin conjugating enzymes to a protein target. Here we re-evaluate the hybrid RING/HECT mechanism used by the E3 family RING-between-RINGs (RBRs) to transfer ubiquitin to substrates. We place RBRs into the context of current knowledge of HECT and RING E3s. Although not as abundant as the other types of E3s (there are only slightly more than a dozen RBR E3s in the human genome), RBRs are conserved in all eukaryotes and play important roles in biology. Re-evaluation of RBR ligases as RING/HECT E3s provokes new questions and challenges the field.
MeSH term(s)	Animals ; Drosophila/metabolism ; Humans ; RING Finger Domains ; Saccharomyces cerevisiae/metabolism ; Ubiquitin-Protein Ligases/chemistry ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
Chemical Substances	Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2012-03-15
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ISSN	1741-7007
ISSN (online)	1741-7007
DOI	10.1186/1741-7007-10-24
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Article ; Online: Following Ariadne's thread

Wenzel Dawn M / Klevit Rachel E

BMC Biology, Vol 10, Iss 1, p

a new perspective on RBR ubiquitin ligases

2012 Volume 24

Abstract: Abstract Ubiquitin signaling pathways rely on E3 ligases for effecting the final transfer of ubiquitin from E2 ubiquitin conjugating enzymes to a protein target. Here we re-evaluate the hybrid RING/HECT mechanism used by the E3 family RING-between-RINGs ( ...

Abstract	Abstract Ubiquitin signaling pathways rely on E3 ligases for effecting the final transfer of ubiquitin from E2 ubiquitin conjugating enzymes to a protein target. Here we re-evaluate the hybrid RING/HECT mechanism used by the E3 family RING-between-RINGs (RBRs) to transfer ubiquitin to substrates. We place RBRs into the context of current knowledge of HECT and RING E3s. Although not as abundant as the other types of E3s (there are only slightly more than a dozen RBR E3s in the human genome), RBRs are conserved in all eukaryotes and play important roles in biology. Re-evaluation of RBR ligases as RING/HECT E3s provokes new questions and challenges the field.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2012-03-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: E2s: structurally economical and functionally replete.

Wenzel, Dawn M / Stoll, Kate E / Klevit, Rachel E

The Biochemical journal

2011 Volume 433, Issue 1, Page(s) 31–42

Abstract: Ubiquitination is a post-translational modification pathway involved in myriad cellular regulation and disease pathways. The Ub (ubiquitin) transfer cascade requires three enzyme activities: a Ub-activating (E1) enzyme, a Ub-conjugating (E2) enzyme, and ... ...

Abstract	Ubiquitination is a post-translational modification pathway involved in myriad cellular regulation and disease pathways. The Ub (ubiquitin) transfer cascade requires three enzyme activities: a Ub-activating (E1) enzyme, a Ub-conjugating (E2) enzyme, and a Ub ligase (E3). Because the E2 is responsible both for E3 selection and substrate modification, E2s function at the heart of the Ub transfer pathway and are responsible for much of the diversity of Ub cellular signalling. There are currently over 90 three-dimensional structures for E2s, both alone and in complex with protein binding partners, providing a wealth of information regarding how E2s are recognized by a wide variety of proteins. In the present review, we describe the prototypical E2-E3 interface and discuss limitations of current methods to identify cognate E2-E3 partners. We present non-canonical E2-protein interactions and highlight the economy of E2s in their ability to facilitate many protein-protein interactions at nearly every surface on their relatively small and compact catalytic domain. Lastly, we compare the structures of conjugated E2~Ub species, their unique protein interactions and the mechanistic insights provided by species that are poised to transfer Ub.
MeSH term(s)	Protein Binding ; Protein Interaction Domains and Motifs ; Ubiquitin-Conjugating Enzymes/chemistry ; Ubiquitin-Conjugating Enzymes/metabolism ; Ubiquitin-Conjugating Enzymes/physiology ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitin-Protein Ligases/physiology ; Ubiquitination
Chemical Substances	Ubiquitin-Conjugating Enzymes (EC 2.3.2.23) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2011-01-19
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BJ20100985
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Article ; Online: Biochemical and structural characterization of the ubiquitin-conjugating enzyme UBE2W reveals the formation of a noncovalent homodimer.

Vittal, Vinayak / Wenzel, Dawn M / Brzovic, Peter S / Klevit, Rachel E

Cell biochemistry and biophysics

2013 Volume 67, Issue 1, Page(s) 103–110

Abstract: The biochemical and structural characterization of ubiquitin-conjugating enzymes (E2s) over the past 30 years has fostered important insights into ubiquitin transfer mechanisms. Although many of these enzymes share high sequence and structural ... ...

Abstract	The biochemical and structural characterization of ubiquitin-conjugating enzymes (E2s) over the past 30 years has fostered important insights into ubiquitin transfer mechanisms. Although many of these enzymes share high sequence and structural conservation, their functional roles in the cell are decidedly diverse. Here, we report that the mono-ubiquitinating E2 UBE2W forms a homodimer using two distinct protein surfaces. Dimerization is primarily driven by residues in the ß-sheet region and Loops 4 and 7 of the catalytic domain. Mutation of two residues in the catalytic domain of UBE2W is capable of disrupting UBE2W homodimer formation, however, we find that dimerization of this E2 is not required for its ubiquitin transfer activity. In addition, residues in the C-terminal region, although not compulsory for the dimerization of UBE2W, play an ancillary role in the dimer interface. In all current E2 structures, the C-terminal helix of the UBC domain is at least 15Å away from the primary dimerization surface shown here for UBE2W. This leads to the proposal that the C-terminal region of UBE2W adopts a noncanonical position that places it closer to the UBC ß-sheet, providing the first indication that at least some E2s adopt C-terminal conformations different from the canonical structures observed to date.
MeSH term(s)	Catalytic Domain ; Dimerization ; Humans ; Magnetic Resonance Spectroscopy ; Mutation ; Protein Structure, Secondary ; Recombinant Proteins/biosynthesis ; Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Ubiquitin-Conjugating Enzymes/chemistry ; Ubiquitin-Conjugating Enzymes/genetics ; Ubiquitin-Conjugating Enzymes/metabolism
Chemical Substances	Recombinant Proteins ; UBE2W protein, human (EC 2.3.2.23) ; Ubiquitin-Conjugating Enzymes (EC 2.3.2.23)
Language	English
Publishing date	2013-05-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1357904-6
ISSN	1559-0283 ; 1085-9195
ISSN (online)	1559-0283
ISSN	1085-9195
DOI	10.1007/s12013-013-9633-5
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Article: Long-term environmental enrichment is associated with better fornix microstructure in older adults.

Klimecki, Olga M / Liebscher, Maxie / Gaubert, Malo / Hayek, Dayana / Zarucha, Alexis / Dyrba, Martin / Bartels, Claudia / Buerger, Katharina / Butryn, Michaela / Dechent, Peter / Dobisch, Laura / Ewers, Michael / Fliessbach, Klaus / Freiesleben, Silka Dawn / Glanz, Wenzel / Hetzer, Stefan / Janowitz, Daniel / Kilimann, Ingo / Kleineidam, Luca /

Frontiers in aging neuroscience

2023 Volume 15, Page(s) 1170879

Abstract: Background: Sustained environmental enrichment (EE) through a variety of leisure activities may decrease the risk of developing Alzheimer's disease. This cross-sectional cohort study investigated the association between long-term EE in young adulthood ... ...

Abstract	Background: Sustained environmental enrichment (EE) through a variety of leisure activities may decrease the risk of developing Alzheimer's disease. This cross-sectional cohort study investigated the association between long-term EE in young adulthood through middle life and microstructure of fiber tracts associated with the memory system in older adults. Methods: N Results: Reported participation in higher long-term EE was associated with greater fornix microstructure, as indicated by higher FA (standardized β = 0.117, Conclusion: Our findings suggest that sustained participation in a greater variety of leisure activities relates to preserved WM microstructure in the memory system in older adults. This could be facilitated by the multimodal stimulation associated with the engagement in a physically, intellectually, and socially enriched lifestyle. Longitudinal studies will be needed to support this assumption.
Language	English
Publishing date	2023-08-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2023.1170879
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Article ; Online: A cancer-associated polymorphism in ESCRT-III disrupts the abscission checkpoint and promotes genome instability.

Sadler, Jessica B A / Wenzel, Dawn M / Strohacker, Lauren K / Guindo-Martínez, Marta / Alam, Steven L / Mercader, Josep M / Torrents, David / Ullman, Katharine S / Sundquist, Wesley I / Martin-Serrano, Juan

Proceedings of the National Academy of Sciences of the United States of America

2018 Volume 115, Issue 38, Page(s) E8900–E8908

Abstract: Cytokinetic abscission facilitates the irreversible separation of daughter cells. This process requires the endosomal-sorting complexes required for transport (ESCRT) machinery and is tightly regulated by charged multivesicular body protein 4C (CHMP4C), ... ...

Abstract	Cytokinetic abscission facilitates the irreversible separation of daughter cells. This process requires the endosomal-sorting complexes required for transport (ESCRT) machinery and is tightly regulated by charged multivesicular body protein 4C (CHMP4C), an ESCRT-III subunit that engages the abscission checkpoint (NoCut) in response to mitotic problems such as persisting chromatin bridges within the midbody. Importantly, a human polymorphism in CHMP4C (rs35094336, CHMP4C
MeSH term(s)	Calcium-Binding Proteins/metabolism ; Carcinogenesis/genetics ; Cell Cycle Checkpoints/genetics ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Chromatin/metabolism ; Crystallography, X-Ray ; DNA Damage/genetics ; DNA Replication/genetics ; Endosomal Sorting Complexes Required for Transport/genetics ; Endosomal Sorting Complexes Required for Transport/metabolism ; Genetic Predisposition to Disease/genetics ; Genomic Instability/genetics ; Humans ; Mitosis/genetics ; Neoplasms/genetics ; Phosphorylation ; Polymorphism, Genetic ; RNA, Small Interfering/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	CHMP4C protein, human ; Calcium-Binding Proteins ; Cell Cycle Proteins ; Chromatin ; Endosomal Sorting Complexes Required for Transport ; PDCD6IP protein, human ; RNA, Small Interfering ; TP53 protein, human ; Tumor Suppressor Protein p53
Language	English
Publishing date	2018-09-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1805504115
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Article ; Online: UBCH7 reactivity profile reveals parkin and HHARI to be RING/HECT hybrids.

Wenzel, Dawn M / Lissounov, Alexei / Brzovic, Peter S / Klevit, Rachel E

Nature

2011 Volume 474, Issue 7349, Page(s) 105–108

Abstract: Although the functional interaction between ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s) is essential in ubiquitin (Ub) signalling, the criteria that define an active E2-E3 pair are not well established. The human E2 UBCH7 (also known ... ...

Abstract	Although the functional interaction between ubiquitin-conjugating enzymes (E2s) and ubiquitin ligases (E3s) is essential in ubiquitin (Ub) signalling, the criteria that define an active E2-E3 pair are not well established. The human E2 UBCH7 (also known as UBE2L3) shows broad specificity for HECT-type E3s, but often fails to function with RING E3s in vitro despite forming specific complexes. Structural comparisons of inactive UBCH7-RING complexes with active UBCH5-RING complexes reveal no defining differences, highlighting a gap in our understanding of Ub transfer. Here we show that, unlike many E2s that transfer Ub with RINGs, UBCH7 lacks intrinsic, E3-independent reactivity with lysine, explaining its preference for HECTs. Despite lacking lysine reactivity, UBCH7 exhibits activity with the RING-in-between-RING (RBR) family of E3s that includes parkin (also known as PARK2) and human homologue of ariadne (HHARI; also known as ARIH1). Found in all eukaryotes, RBRs regulate processes such as translation and immune signalling. RBRs contain a canonical C3HC4-type RING, followed by two conserved Cys/His-rich Zn(2+)-binding domains, in-between-RING (IBR) and RING2 domains, which together define this E3 family. We show that RBRs function like RING/HECT hybrids: they bind E2s via a RING domain, but transfer Ub through an obligate thioester-linked Ub (denoted ∼Ub), requiring a conserved cysteine residue in RING2. Our results define the functional cadre of E3s for UBCH7, an E2 involved in cell proliferation and immune function, and indicate a novel mechanism for an entire class of E3s.
MeSH term(s)	Amino Acid Sequence ; Carrier Proteins/chemistry ; Carrier Proteins/metabolism ; Catalytic Domain ; Cysteine/chemistry ; Humans ; Lysine/metabolism ; Molecular Sequence Data ; Mutant Chimeric Proteins/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Sequence Alignment ; Ubiquitin/metabolism ; Ubiquitin-Conjugating Enzymes/chemistry ; Ubiquitin-Conjugating Enzymes/metabolism ; Ubiquitin-Protein Ligases/chemistry ; Ubiquitin-Protein Ligases/metabolism
Chemical Substances	Carrier Proteins ; Mutant Chimeric Proteins ; Ubiquitin ; UBE2L3 protein, human (EC 2.3.2.23) ; Ubiquitin-Conjugating Enzymes (EC 2.3.2.23) ; ARIH1 protein, human (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; parkin protein (EC 2.3.2.27) ; Lysine (K3Z4F929H6) ; Cysteine (K848JZ4886)
Language	English
Publishing date	2011-05-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature09966
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Article ; Online: ULK3 regulates cytokinetic abscission by phosphorylating ESCRT-III proteins.

Caballe, Anna / Wenzel, Dawn M / Agromayor, Monica / Alam, Steven L / Skalicky, Jack J / Kloc, Magdalena / Carlton, Jeremy G / Labrador, Leticia / Sundquist, Wesley I / Martin-Serrano, Juan

eLife

2015 Volume 4, Page(s) e06547

Abstract: The endosomal sorting complexes required for transport (ESCRT) machinery mediates the physical separation between daughter cells during cytokinetic abscission. This process is regulated by the abscission checkpoint, a genome protection mechanism that ... ...

Abstract	The endosomal sorting complexes required for transport (ESCRT) machinery mediates the physical separation between daughter cells during cytokinetic abscission. This process is regulated by the abscission checkpoint, a genome protection mechanism that relies on Aurora B and the ESCRT-III subunit CHMP4C to delay abscission in response to chromosome missegregation. In this study, we show that Unc-51-like kinase 3 (ULK3) phosphorylates and binds ESCRT-III subunits via tandem MIT domains, and thereby, delays abscission in response to lagging chromosomes, nuclear pore defects, and tension forces at the midbody. Our structural and biochemical studies reveal an unusually tight interaction between ULK3 and IST1, an ESCRT-III subunit required for abscission. We also demonstrate that IST1 phosphorylation by ULK3 is an essential signal required to sustain the abscission checkpoint and that ULK3 and CHMP4C are functionally linked components of the timer that controls abscission in multiple physiological situations.
MeSH term(s)	Cell Line ; Cytokinesis ; Endosomal Sorting Complexes Required for Transport/metabolism ; Humans ; Oncogene Proteins/metabolism ; Phosphorylation ; Protein Binding ; Protein Processing, Post-Translational ; Protein-Serine-Threonine Kinases/metabolism
Chemical Substances	CHMP4C protein, human ; Endosomal Sorting Complexes Required for Transport ; IST1 protein, human ; Oncogene Proteins ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; ULK3 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2015-05-26
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.06547
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