title: A divalent ion is crucial in the structure and dominant-negative function of ID proteins, a class of helix-loop-helix transcription regulators.
abstract: Inhibitors 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 2.1Å 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.
authors.affiliation: Laboratory for Structural Biochemistry, Genome Institute of Singapore, Singapore, Singapore.
authors.forename: Marie Vivian
authors.initials: MV
authors.lastname: Wong
authors.forename: Sizun
authors.initials: S
authors.lastname: Jiang
authors.forename: Paaventhan
authors.initials: P
authors.lastname: Palasingam
authors.forename: Prasanna R
authors.initials: PR
authors.lastname: Kolatkar
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002413:Cations, Divalent / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D024202:Electrophoretic Mobility Shift Assay; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051796:Inhibitor of Differentiation Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D017570:MyoD Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D058127:Transcription Factor 3 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000596:Amino Acids; D002413:Cations, Divalent; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D051796:Inhibitor of Differentiation Proteins; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D058127:Transcription Factor 3; C075640:ID3 protein, human; D002118:Calcium