Repository logo

Complex domain interactions regulate stability and activity of closely related proneural transcription factors.



Change log


McDowell, Gary S 
Hardwick, Laura JA 


Characterising post-translational regulation of key transcriptional activators is crucial for understanding how cell division and differentiation are coordinated in developing organisms and cycling cells. One important mode of protein post-translational control is by regulation of half-life via ubiquitin-mediated proteolysis. Two key basic Helix-Loop-Helix transcription factors, Neurogenin 2 (Ngn2) and NeuroD, play central roles in development of the central nervous system but despite their homology, Ngn2 is a highly unstable protein whilst NeuroD is, by comparison, very stable. The basis for and the consequences of the difference in stability of these two structurally and functionally related proteins has not been explored. Here we see that ubiquitylation alone does not determine Ngn2 or NeuroD stability. By making chimeric proteins, we see that the N-terminus of NeuroD in particular has a stabilising effect, whilst despite their high levels of homology, the most conserved bHLH domains of these proneural proteins alone can confer significant changes in protein stability. Despite widely differing stabilities of Ngn2, NeuroD and the chimeric proteins composed of domains of both, there is little correlation between protein half-life and ability to drive neuronal differentiation. Therefore, we conclude that despite significant homology between Ngn2 and NeuroD, the regulation of their stability differs markedly and moreover, stability/instability of the proteins is not a direct correlate of their activity.



Neurogenesis, Proneural, Proteasomal degradation, Ubiquitylation, Xenopus, Amino Acid Sequence, Base Sequence, DNA Primers, Half-Life, Molecular Sequence Data, Mutagenesis, Site-Directed, Polymerase Chain Reaction, Protein Unfolding, Proteolysis, Sequence Homology, Amino Acid, Transcription Factors

Journal Title

Biochem Biophys Res Commun

Conference Name

Journal ISSN


Volume Title


Elsevier BV
Medical Research Council (G0700758)
Medical Research Council (G0700758/1)
Many thanks to Jon Vosper, Ryan Roark and Chris Hindley for helpful discussions. This work was supported by MRC Research Q23 Grant G0700758 (AP), and two MRC DTA Studentships (GM and LH).