How the ends signal the end: Regulation by E3 ubiquitin ligases recognizing protein termini

Sherpa, Dawafuti; Chrustowicz, Jakub; Schulman, Brenda A.

doi:10.1016/j.molcel.2022.02.004

Cited by 55 publications

(40 citation statements)

References 101 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The distribution of E3 ligases in cell cycle contributes to the inadequate degradation efficiency of dAurA425 and dAurA450. Other reasons for the low efficiency of dAurA425 and dAurA450 such as the “degron” motifs [ 62 ] recognized by VHL and cIAP1 within AURKA need to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

A Temporal PROTAC Cocktail‐Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells

et al. 2022

View full text Add to dashboard Cite

AURKA is a potential kinase target in various malignancies. The kinase‐independent oncogenic functions partially disclose the inadequate efficacy of the kinase inhibitor in a Phase III clinical trial. Simultaneously targeting the catalytic and noncatalytic functions of AURKA may be a feasible approach. Here, a set of AURKA proteolysis targeting chimeras (PROTACs) are developed. The CRBN‐based dAurA383 preferentially degrades the highly abundant mitotic AURKA, while cIAP‐based dAurA450 degrades the lowly abundant interphase AURKA in acute myeloid leukemia (AML) cells. The proteomic and transcriptomic analyses indicate that dAurA383 triggers the “mitotic cell cycle” and “stem cell” processes, while dAurA450 inhibits the “MYC/E2F targets” and “stem cell” processes. dAurA383 and dAurA450 are combined as a PROTAC cocktail. The cocktail effectively degrades AURKA, relieves the hook effect, and synergistically inhibits AML stem cells. Furthermore, the PROTAC cocktail induces AML regression in a xenograft mouse model and primary patient blasts. These findings establish the PROTAC cocktail as a promising spatial‐temporal drug administration strategy to sequentially eliminate the multifaceted functions of oncoproteins, relieve the hook effect, and prevent cancer stem cell‐mediated drug resistance.

show abstract

Section: Discussionmentioning

confidence: 99%

A Temporal PROTAC Cocktail‐Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells

et al. 2022

View full text Add to dashboard Cite

show abstract

“…In S. cerevisiae , Gid4 and Gid10 antiparallel β-barrels recognize N-terminal prolines as part of the Pro/N-degron pathway ( Figure 2 h,i) [ 3 , 9 , 12 , 14 , 35 , 36 , 37 ]. A PGLW peptide, resembling the yeast Pro/N-degron, fits snugly at the bottom of a deep and narrow binding cleft in the human GID4 β-barrel in a precise position to mediate a network of hydrogen bonds [ 35 ].…”

Section: The Basics: Gid/ctlh Complex Composition Characteristics And...mentioning

confidence: 99%

“…A structurally similar six-blade kelch repeat is predicted for muskelin. Both WD40 and kelch β-propellers facilitate protein–protein interactions or protein–DNA interactions and are often found in multi-subunit complexes, including other E3 ligases [ 3 , 41 ]. Additionally, muskelin has a discoidin domain at the N-terminus before the LisH domain ( Figure 2 a,g) [ 11 ].…”

Section: The Basics: Gid/ctlh Complex Composition Characteristics And...mentioning

confidence: 99%

“…Most of the CTLH complex protein interaction domains described above act as substrate recruitment modules in other E3 ligase proteins [ 3 ]. At present, however, a substrate recruitment function has only been demonstrated for the yeast Gid4/Gid10 β-barrel.…”

Section: The Basics: Gid/ctlh Complex Composition Characteristics And...mentioning

confidence: 99%

“…Ubiquitination regulates proteome dynamics with exquisite specificity [ 1 , 2 ]. This is largely achieved by E3 ligases, which function to recruit substrates for ubiquitin (Ub) modification usually by recognizing short linear motifs (called degrons) in the target [ 3 , 4 , 5 ]. Over 600 E3 ligases exist that include either a RING (Really Interesting New Gene) or HECT (Homologous to the E6AP Carboxyl Terminus) domain that facilitates Ub transfer from an E2 conjugating enzyme to a substrate.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Structural and Functional Insights into GID/CTLH E3 Ligase Complexes

Maitland

Lajoie

Shaw

et al. 2022

IJMS

View full text Add to dashboard Cite

Multi-subunit E3 ligases facilitate ubiquitin transfer by coordinating various substrate receptor subunits with a single catalytic center. Small molecules inducing targeted protein degradation have exploited such complexes, proving successful as therapeutics against previously undruggable targets. The C-terminal to LisH (CTLH) complex, also called the glucose-induced degradation deficient (GID) complex, is a multi-subunit E3 ligase complex highly conserved from Saccharomyces cerevisiae to humans, with roles in fundamental pathways controlling homeostasis and development in several species. However, we are only beginning to understand its mechanistic basis. Here, we review the literature of the CTLH complex from all organisms and place previous findings on individual subunits into context with recent breakthroughs on its structure and function.

show abstract

Skraban‐Deardorff intellectual disability syndrome‐associated mutations in WDR26 impair CTLH E3 complex assembly

Gross,

Müller,

Chrustowicz

et al. 2024

FEBS Letters

Self Cite

View full text Add to dashboard Cite

Patients with Skraban‐Deardorff syndrome (SKDEAS), a neurodevelopmental syndrome associated with a spectrum of developmental and intellectual delays and disabilities, harbor diverse mutations in WDR26, encoding a subunit of the multiprotein CTLH E3 ubiquitin ligase complex. Structural studies revealed that homodimers of WDR26 bridge two core‐CTLH E3 complexes to generate giant, hollow oval‐shaped supramolecular CTLH E3 assemblies. Additionally, WDR26 mediates CTLH E3 complex binding to subunit YPEL5 and functions as substrate receptor for the transcriptional repressor HBP1. Here, we mapped SKDEAS‐associated mutations on a WDR26 structural model and tested their functionality in complementation studies using genetically engineered human cells lacking CTLH E3 supramolecular assemblies. Despite the diversity of mutations, 15 of 16 tested mutants impaired at least one CTLH E3 complex function contributing to complex assembly and interactions, thus providing first mechanistic insights into SKDEAS pathology.

show abstract

How the ends signal the end: Regulation by E3 ubiquitin ligases recognizing protein termini

Cited by 55 publications

References 101 publications

A Temporal PROTAC Cocktail‐Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells

A Temporal PROTAC Cocktail‐Mediated Sequential Degradation of AURKA Abrogates Acute Myeloid Leukemia Stem Cells

Structural and Functional Insights into GID/CTLH E3 Ligase Complexes

Skraban‐Deardorff intellectual disability syndrome‐associated mutations in WDR26 impair CTLH E3 complex assembly

Contact Info

Product

Resources

About