Higher-order SPOP assembly reveals a basis for cancer mutant dysregulation

Cuneo, M.J.; O’Flynn, Brian G.; Lo, Yi-Ching; Sabri, Nafiseh; Mittag, Tanja

doi:10.1016/j.molcel.2022.12.033

Cited by 16 publications

(12 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the roles of other mutations differentially impact the stability of various substrates. Potential mechanistic effects have only emerged recently, with the discovery that SPOP forms self-assembled filaments, and the relative arrangements of domains in the self-assemblies may differ for different cancer mutants [60,61]. The different filaments show distinct stabilities, and presumably also control recruitment of particular substrates although this latter functionality remains to be clearly elucidated.…”

Section: Discussionmentioning

confidence: 99%

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

Gross,

Müller,

Chrustowicz

et al. 2024

FEBS Letters

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

Section: Discussionmentioning

confidence: 99%

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

Gross,

Müller,

Chrustowicz

et al. 2024

FEBS Letters

View full text Add to dashboard Cite

show abstract

“…For instance, neddylation can switch the autoinhibited tetrameric CRL4 ADCAF1 into an activated dimeric state 50 . Considering that CRL3s exist not only in the dimeric state but also in higher oligomeric state, such as oligomeric SPOP, pentameric CRL3 KCTD5 , tetrameric and octameric CRL3 KBTBD2 51 – 53 , it is worth to further investigating whether the CUL3 NA motif alone or together with neddylation can affect the higher oligomer state of CRL3s.…”

Section: Discussionmentioning

confidence: 99%

A conserved N-terminal motif of CUL3 contributes to assembly and E3 ligase activity of CRL3KLHL22

Wang,

Liang,

Dai

et al. 2024

Nat Commun

View full text Add to dashboard Cite

The CUL3-RING E3 ubiquitin ligases (CRL3s) play an essential role in response to extracellular nutrition and stress stimuli. The ubiquitin ligase function of CRL3s is activated through dimerization. However, how and why such a dimeric assembly is required for its ligase activity remains elusive. Here, we report the cryo-EM structure of the dimeric CRL3KLHL22 complex and reveal a conserved N-terminal motif in CUL3 that contributes to the dimerization assembly and the E3 ligase activity of CRL3KLHL22. We show that deletion of the CUL3 N-terminal motif impairs dimeric assembly and the E3 ligase activity of both CRL3KLHL22 and several other CRL3s. In addition, we found that the dynamics of dimeric assembly of CRL3KLHL22 generates a variable ubiquitination zone, potentially facilitating substrate recognition and ubiquitination. These findings demonstrate that a CUL3 N-terminal motif participates in the assembly process and provide insights into the assembly and activation of CRL3s.

show abstract

“…The CRL3 family, defined by the inclusion of cullin3 (CUL3), can directly engage over 100 different SRs that typically combine a BTB CUL3-binding domain and a substrate-binding domain in a single polypeptide (3). Notably, BTB domains can self-associate into stable dimers, pentamers and oligomers (4)(5)(6)(7)(8)(9) and thus drive the multimerization of CRL3 complexes. While multivalency is not a unique feature of the CRL3s (10), most structures of CRL complexes reported to date have involved truncated components that result in monovalent complexes (11,12).…”

Section: Introductionmentioning

confidence: 99%

Structure and dynamics of a pentameric KCTD5/Cullin3/Gβγ E3 ubiquitin ligase complex

Nguyen,

Rath,

Devost

et al. 2023

Preprint

View full text Add to dashboard Cite

Heterotrimeric G proteins can be regulated by post-translational modifications, including ubiquitylation. KCTD5, a pentameric substrate receptor protein consisting of an N-terminal BTB domain and a C-terminal domain (CTD), engages CUL3 to form the central scaffold of a cullin-RING E3 ligase complex (CRL3KCTD5) that ubiquitylates Gβγ and reduces Gβγ protein levels in cells. The cryo-EM structure of a 5:5:5 KCTD5/CUL3NTD/Gβ1γ2 assembly reveals a highly dynamic complex with rotations of over 60° between the KCTD5BTB/CUL3NTD and KCTD5CTD/Gβγ moieties of the structure. CRL3KCTD5 engages the E3 ligase ARIH1 to ubiquitylate Gβγ in an E3-E3 super-assembly, and extension of the structure to include full-length CUL3 with RBX1 and an ARIH1~ubiquitin conjugate reveals that some conformational states position the ARIH1~ubiquitin thioester bond to within 10 Å of lysine-23 of Gβ and likely represent priming complexes. Most previously described CRL/substrate structures have consisted of monovalent complexes and have involved flexible peptide substrates. The structure of the KCTD5/CUL3NTD/Gβγ complex shows that the oligomerization of a substrate receptor can generate a polyvalent E3 ligase complex and that the internal dynamics of the substrate receptor can position a structured target for ubiquitylation in a CRL3 complex.

show abstract

Higher-order SPOP assembly reveals a basis for cancer mutant dysregulation

Cited by 16 publications

References 50 publications

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

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

A conserved N-terminal motif of CUL3 contributes to assembly and E3 ligase activity of CRL3KLHL22

Structure and dynamics of a pentameric KCTD5/Cullin3/Gβγ E3 ubiquitin ligase complex

Contact Info

Product

Resources

About