4aya | pdb_00004aya
Crystal structure of ID2 HLH homodimer at 2.1A resolution
Structural highlights
Function[ID2_HUMAN] Transcriptional regulator (lacking a basic DNA binding domain) which negatively regulates the basic helix-loop-helix (bHLH) transcription factors by forming heterodimers and inhibiting their DNA binding and transcriptional activity. Implicated in regulating a variety of cellular processes, including cellular growth, senescence, differentiation, apoptosis, angiogenesis, and neoplastic transformation. Inhibits skeletal muscle and cardiac myocyte differentiation. Regulates the circadian clock by repressing the transcriptional activator activity of the CLOCK-ARNTL/BMAL1 heterodimer. Restricts the CLOCK and ARNTL/BMAL1 localization to the cytoplasm. Plays a role in both the input and output pathways of the circadian clock: in the input component, is involved in modulating the magnitude of photic entrainment and in the output component, contributes to the regulation of a variety of liver clock-controlled genes involved in lipid metabolism.[1] Publication Abstract from PubMedInhibitors of DNA binding and differentiation (ID) proteins, a dominant-negative group of helix-loop-helix (HLH) transcription regulators, are well-characterized key players in cellular fate determination during development in mammals as well as Drosophila. Although not oncogenes themselves, their upregulation by various oncogenic proteins (such as Ras, Myc) and their inhibitory effects on cell cycle proteins (such as pRb) hint at their possible roles in tumorigenesis. Furthermore, their potency as inhibitors of cellular differentiation, through their heterodimerization with subsequent inactivation of the ubiquitous E proteins, suggest possible novel roles in engineering induced pluripotent stem cells (iPSCs). We present the high-resolution 2.1A crystal structure of ID2 (HLH domain), coupled with novel biochemical insights in the presence of a divalent ion, possibly calcium (Ca2+), in the loop of ID proteins, which appear to be crucial for the structure and activity of ID proteins. These new insights will pave the way for new rational drug designs, in addition to current synthetic peptide options, against this potent player in tumorigenesis as well as more efficient ways for stem cells reprogramming. A Divalent Ion Is Crucial in the Structure and Dominant-Negative Function of ID Proteins, a Class of Helix-Loop-Helix Transcription Regulators.,Wong MV, Jiang S, Palasingam P, Kolatkar PR PLoS One. 2012;7(10):e48591. doi: 10.1371/journal.pone.0048591. Epub 2012 Oct 30. PMID:23119064[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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