Research Article

Dimerization quality control ensures neuronal development and survival

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Science  12 Oct 2018:
Vol. 362, Issue 6411, eaap8236
DOI: 10.1126/science.aap8236

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A way to prevent deadly interaction

Many metazoan proteins form oligomers, which is often mediated by modular domains such as BTB domains. Mena et al. now describe a quality control pathway they term dimerization quality control (DQC) (see the Perspective by Herhaus and Dikic). DQC monitors and prevents aberrant dimerization of BTB domain–containing proteins. The system relies on FBXL17, an adaptor protein that recruits an E3 ligase that specifically ubiquitylates nonfunctional BTB heterodimers, triggering their degradation. FBXL17 accesses a degradation signal at the BTB dimer interface in nonphysiological, nonfunctional complexes. The loss of DQC from Xenopus laevis embryos leads to lethal neurodevelopmental defects.

Science, this issue p. eaap8236; see also p. 151

Structured Abstract


Protein complex formation is at the heart of all metazoan signal transduction networks. Facilitating cellular information flow, modular BTB domains, leucine zippers, or coiled coils have been reused in many proteins, where they often mediate crucial homodimerization events. While mutation of a single allele encoding homodimeric proteins might poison signaling complexes, aberrant heterodimerization between related modules can also inhibit or alter the output of signal transduction cascades. Whether cells detect and eliminate protein complexes of aberrant composition has remained unknown.

The globular BTB domain is found in ~220 human proteins that function as substrate adapters of CUL3 E3 ligases, transcription factors, or membrane channels. Proteins containing homodimeric BTB domains, such as KEAP1, KLHL3, KBTBD8, or BCL6, are essential for metazoan development, and their mutation or aberrant expression causes hypertension, cancer, or neurodegeneration. As it is not understood how organisms control the expression or activity of homodimeric BTB proteins, the BTB domain provides a physiologically important model to dissect the regulation of recurrent interaction modules.


To identify regulatory mechanisms that impinge on modular interaction domains, we searched for shared binding partners of BTB proteins. Having found an E3 ligase that targets multiple BTB proteins for proteasomal degradation, we used biochemical reconstitution and protein complex engineering to dissect the underlying molecular control mechanism. Finally, we relied on Xenopus laevis embryos to study the organismal consequences of aberrant regulation of recurrent protein interaction modules.


Affinity purification and mass spectrometry experiments revealed that many BTB proteins heterodimerize, but also interacted with FBXL17, the substrate adapter of the SCFFBXL17 E3 ligase. SCFFBXL17 catalyzed the polyubiquitylation of BTB proteins to trigger their proteasomal degradation. SCFFBXL17 is therefore a rare example of an E3 ligase that targets a domain shared by many proteins, rather than a specific substrate.

As shown by biochemical reconstitution and affinity purification from cells and animals, SCFFBXL17 is a quality control enzyme that detects and ubiquitylates inactive BTB heterodimers, yet ignores active homodimers of the same domains. Accordingly, the loss of FBXL17 increased heterodimerization of BTB proteins, yet at the same time reduced the ability of BTB proteins to engage their downstream targets. SCFFBXL17 therefore ensures that only functional BTB dimers are present in cells, an activity that we refer to as dimerization quality control (DQC).

Depletion of FBXL17 in differentiating human embryonic stem cells showed that DQC prevented heterodimerization of KBTBD8, a BTB protein that is an essential regulator of neural crest specification. In line with this observation, the loss of DQC from Xenopus laevis embryos interfered with the differentiation, function, and survival of cells of the central and peripheral nervous system, including the neural crest. By contrast, somitogenesis or general body plan formation were initially unaffected. Similar to other quality control networks, the loss of DQC thus caused specific neuronal phenotypes. However, in addition to the known consequence of muted quality control, i.e. premature neuronal death, the effects of aberrant DQC were already observed early during differentiation.


We discovered DQC as a surveillance pathway that detects protein complexes of aberrant composition, rather than protein misfolding. We speculate that other recurrent interaction modules, such as leucine zippers or coiled coils, are monitored by similar DQC networks that rely on distinct E3 ligases. The neuronal phenotypes caused by DQC inactivation point to an active role of quality control in fate decisions in the nervous system. During evolution, DQC appeared at the same time as BTB domains multiplied in the vertebrate genome, suggesting that the ability to eliminate inactive heterodimers formed by related BTB domains contributed to the widespread use of this domain as a dimerization module.

Dimerization quality control eliminates inactive heterodimers of a recurrent interaction module but leaves functional homodimers intact.

SCFFBXL17 selectively ubiquitylates inactive BTB dimers, such as BTB heterodimers or dimers containing mutant BTB domains, which triggers their proteasomal degradation. Functional BTB homodimers escape detection by SCFFBXL17.


Aberrant complex formation by recurrent interaction modules, such as BTB domains, leucine zippers, or coiled coils, can disrupt signal transduction, yet whether cells detect and eliminate complexes of irregular composition is unknown. By searching for regulators of the BTB family, we discovered a quality control pathway that ensures functional dimerization [dimerization quality control (DQC)]. Key to this network is the E3 ligase SCFFBXL17, which selectively binds and ubiquitylates BTB dimers of aberrant composition to trigger their clearance by proteasomal degradation. Underscoring the physiological importance of DQC, SCFFBXL17 is required for the differentiation, function, and survival of neural crest and neuronal cells. We conclude that metazoan organisms actively monitor BTB dimerization, and we predict that distinct E3 ligases similarly control complex formation by other recurrent domains.

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