Relationship between the structure and function of the transcriptional regulator E2A

E proteins are transcriptional regulators that regulate many developmental processes in animals and lymphocytosis and leukemia in Homo sapiens. In particular, E2A, a member of the E protein family, plays a major role in the transcriptional regulatory network that promotes the differentiation and development of B and T lymphocytes. E2A-mediated transcriptional regulation usually requires the formation of E2A dimers, which then bind to coregulators. In this review, we summarize the mechanisms by which E2A participates in transcriptional regulation from a structural perspective. More specifically, the C-terminal helix-loop-helix (HLH) region of the basic HLH (bHLH) domain first dimerizes, and then the activation domains of E2A bind to different coactivators or corepressors in different cell contexts, resulting in histone acetylation or deacetylation, respectively. Then, the N-terminal basic region (b) of the bHLH domain binds to or dissociates from a specific DNA motif (E-box sequence). Last, trans-activation or trans-repression occurs. We also summarize the properties of these E2A domains and their interactions with the domains of other proteins. The feasibility of developing drugs based on these domains is discussed.

Interaction between opposing modes of phospho-regulation of the proneural proteins Ascl1 and Ngn2

From the relatively simple nervous system of Drosophila to the elaborate mammalian cortex, neurogenesis requires exceptional spatial and temporal precision to co-ordinate progenitor cell proliferation and subsequent differentiation to a diverse range of neurons and glia. A limited number of transiently expressed proneural basic-helix-loop-helix (bHLH) transcription factors, for example achaete-scute-complex (as-c) and atonal (ato) in Drosophila and the vertebrate homologues Ascl1 and Neurogenin2 (Ngn2), are able to orchestrate the onset of neuronal determination, context-dependent subtype selection and even influence later aspects of neuronal migration and maturation. Within the last decade, two models have emerged to explain how the temporal activity of proneural determination factors is regulated by phosphorylation at distinct sites. One model describes how cell-cycle associated phosphorylation on multiple sites in the N and C termini of vertebrate proneural proteins limits neuronal differentiation in cycling progenitor cells. A second model describes phosphorylation on a single site in the bHLH domain of Drosophila atonal that acts as a binary switch, where phosphorylation terminates proneural activity. Here we combine activating mutations of phosphorylation sites in the N- and C- termini with an inhibitory phospho-mimetic mutation in the bHLH domain of Ascl1 and Ngn2 proteins, and test their functions in vivo using Xenopus embryos to determine which mode of phospho-regulation dominates. Enhancing activity by preventing N- and C terminal phosphorylation cannot overcome the inhibitory effect of mimicking phosphorylation of the bHLH domain. Thus we have established a hierarchy between these two modes of proneural protein control and suggest a model of temporal regulation for proneural protein activity.

A Key For Hypoxia Genetic Adaptation In Alpaca Could Be A HIF1A Truncated bHLH Protein Domain

Animals exposed to hypoxia, triggers a physiological response via Hypoxia Inducible Factors (HIF1). In this study, we have evidenced the existence of genetic events that caused the loss of most of the bHLH domain in HIF1A proteins borne by Alpaca and other members of the Cetartiodactyla superorder. In these truncate domains, some stop codons are found at identical nucleotide positions in both, Artiodactyls and Cetaceans, indicating that mutations originating the truncated domains occurs before their divergence about 55 million years ago. The relevance of this findings for adaptation of Alpacas to hypoxia of high altitude conditions are discussed.

HEY1 functions are regulated by its phosphorylation at Ser-68

HEY1-dependent activation of the p53 tumour suppressor pathway can be inhibited through direct phosphorylation of HEY1 at Ser-68 located in the bHLH domain. STK38 and STK38L serine/threonine kinases can phosphorylate HEY1 Ser-68 and could modulate its biological function.