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Last update 08 May 2025

KBTBD4

Last update 08 May 2025

Basic Info

Synonyms

BKLHD4, BTB and kelch domain-containing protein 4, FLJ10450

+ [4]

Introduction

Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex which targets CoREST corepressor complex components RCOR1, KDM1A/LSD1 and HDAC2 for proteasomal degradation (PubMed:33417871). RCOR1 is likely to be the primary target while degradation of KDM1A and HDAC2 is likely due to their association with RCOR1 (PubMed:33417871). Also targets RCOR3, MIER2 and MIER3 for proteasomal degradation as well as associated proteins ZNF217 and RREB1 (PubMed:36997086). Degradation is dependent on the presence of an ELM2 domain in the target proteins (PubMed:36997086).

Drugs associated with KBTBD4

UM171

Target

HDAC1 x HDAC2 x KBTBD4

Mechanism

HDAC1 inhibitors [+2]

Active Org.

University of Sao Paulo [+1]

Originator Org.

University of Sao Paulo

Active Indication

Telomere Syndrome [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with KBTBD4

100 Translational Medicine associated with KBTBD4

0 Patents (Medical) associated with KBTBD4

Literatures (Medical) associated with KBTBD4

06 Mar 2025·Nature

Converging mechanism of UM171 and KBTBD4 neomorphic cancer mutations

Article

Author: Payne, N Connor ; Jiang, Hanjie ; Yeo, Megan J R ; Lee, Ceejay ; Batts, Melissa ; Nam, Eunju ; Kwok, Hui Si ; Cole, Philip A ; D'Angiolella, Vincenzo ; Zhang, Olivia ; Mao, Haibin ; Liau, Brian B ; Northcott, Paul A ; Paul, Leena ; Li, Yiran ; Hadley, Jennifer L ; Lin, Hong ; Tao, Ran ; Harry, Stefan A ; Zheng, Ning ; Gosavi, Pallavi M ; Xie, Xiaowen ; Mazitschek, Ralph

AbstractCancer mutations can create neomorphic protein–protein interactions to drive aberrant function1,2. As a substrate receptor of the CULLIN3-RING E3 ubiquitin ligase complex, KBTBD4 is recurrently mutated in medulloblastoma3, the most common embryonal brain tumour in children4. These mutations impart gain-of-function to KBTBD4 to induce aberrant degradation of the transcriptional corepressor CoREST5. However, their mechanism remains unresolved. Here we establish that KBTBD4 mutations promote CoREST degradation through engaging HDAC1/2 as the direct target of the mutant substrate receptor. Using deep mutational scanning, we chart the mutational landscape of the KBTBD4 cancer hotspot, revealing distinct preferences by which insertions and substitutions can promote gain-of-function and the critical residues involved in the hotspot interaction. Cryo-electron microscopy analysis of two distinct KBTBD4 cancer mutants bound to LSD1–HDAC1–CoREST reveals that a KBTBD4 homodimer asymmetrically engages HDAC1 with two KELCH-repeat β-propeller domains. The interface between HDAC1 and one of the KBTBD4 β-propellers is stabilized by the medulloblastoma mutations, which insert a bulky side chain into the HDAC1 active site pocket. Our structural and mutational analyses inform how this hotspot E3–neosubstrate interface can be chemically modulated. First, we unveil a converging shape-complementarity-based mechanism between gain-of-function E3 mutations and a molecular glue degrader, UM171. Second, we demonstrate that HDAC1/2 inhibitors can block the mutant KBTBD4–HDAC1 interface and proliferation of KBTBD4-mutant medulloblastoma cells. Altogether, our work reveals the structural and mechanistic basis of cancer mutation-driven neomorphic protein–protein interactions.

06 Mar 2025·Nature

UM171 glues asymmetric CRL3–HDAC1/2 assembly to degrade CoREST corepressors

Article

Author: Mao, Haibin ; Gosavi, Pallavi M ; Barakat, Idris A ; Mattevi, Andrea ; Waterbury, Amanda L ; Li, Jiaming ; Yeo, Megan J R ; Zhang, Olivia ; Jiang, Hanjie ; Lee, Kwangwoon ; Nguyen, Khanh ; Harry, Stefan A ; Bar-Peled, Liron ; Wang, Zhipeng A ; Barone, Marco ; Mazitschek, Ralph ; Kwok, Hui Si ; Nam, Eunju ; Chen, Nicholas J ; Carr, Steven A ; Takahashi, Mariko ; Liau, Brian B ; Lee, Ceejay ; Iram, Irtiza ; Zheng, Ning ; Xie, Xiaowen ; Payne, N Connor ; Udeshi, Namrata D ; Cole, Philip A

AbstractUM171 is a potent agonist of ex vivo human haematopoietic stem cell self-renewal1. By co-opting KBTBD4, a substrate receptor of the CUL3–RING E3 ubiquitin ligase (CRL3) complex, UM171 promotes the degradation of the LSD1–CoREST corepressor complex, thereby limiting haematopoietic stem cell attrition2,3. However, the direct target and mechanism of action of UM171 remain unclear. Here we show that UM171 acts as a molecular glue to induce high-affinity interactions between KBTBD4 and HDAC1/2 to promote corepressor degradation. Through proteomics and chemical inhibitor studies, we identify the principal target of UM171 as HDAC1/2. Cryo-electron microscopy analysis of dimeric KBTBD4 bound to UM171 and the LSD1–HDAC1–CoREST complex identifies an asymmetric assembly in which a single UM171 molecule enables a pair of KELCH-repeat propeller domains to recruit the HDAC1 catalytic domain. One KBTBD4 propeller partially masks the rim of the HDAC1 active site, which is exploited by UM171 to extend the E3–neosubstrate interface. The other propeller cooperatively strengthens HDAC1 binding through a distinct interface. The overall CoREST–HDAC1/2–KBTBD4 interaction is further buttressed by the endogenous cofactor inositol hexakisphosphate, which acts as a second molecular glue. The functional relevance of the quaternary complex interaction surfaces is demonstrated by base editor scanning of KBTBD4 and HDAC1. By delineating the direct target of UM171 and its mechanism of action, we reveal how the cooperativity offered by a dimeric CRL3 E3 can be leveraged by a small molecule degrader.

01 Aug 2024·International Journal of Surgical Pathology

A Pineal Parenchymal Tumor of Intermediate Differentiation in an Octogenarian Contains a Rare KBTBD4 Insertion

Article

Author: Zanazzi, George J. ; Simmons, Nathan E. ; Kanter, John H. ; Tafe, Laura J. ; Russo, Gregory A. ; Jones, Victoria M.

Pineal parenchymal tumors are rare central nervous system tumors that pose diagnostic challenges for surgical pathologists. Due to their paucity, their clinicopathologic features are still being defined. We report an 86-year-old woman with a remote history of breast lobular carcinoma who presented with a 2-month neurologic history that included gait instability, blurry vision, and headaches. Magnetic resonance imaging revealed a lobular, heterogeneously enhancing pineal region mass compressing the aqueduct of Sylvius. A biopsy performed concomitant with endoscopic third ventriculostomy consisted of small sheets of cells with eosinophilic to clear cytoplasm, multipolar processes, and ovoid nuclei with stippled chromatin. Whole exome sequencing revealed a small in-frame insertion (duplication) in exon 4 of KBTBD4 (c.931_939dup, p.P311_R313dup/ p.R313_M314insPRR), which has very recently been reported in 2 pineal parenchymal tumors of intermediate differentiation (PPTID). Additionally, variants of uncertain significance in CEBPA (c.863G > C, p.R288P) and MYC (c.655T > C, p.S219P) were identified. Although PPTID is considered a disease of young adulthood, review of 2 institutional cohorts of patients with pineal region tumors revealed that 25% of individuals with PPTID were over 65 years of age. In conclusion, PPTID should be considered in the differential diagnosis of pineal region tumors in older adults.

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KBTBD4

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