The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.

The insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) are highly related receptor tyrosine kinases with a disulfide-linked homodimeric architecture. Ligand binding to the receptor ectodomain triggers tyrosine autophosphorylation of the cytoplasmic domains, which stimulates catalytic activity and creates recruitment sites for downstream signalling proteins. Whether the two phosphorylated tyrosine kinase domains within the receptor dimer function independently or cooperatively to phosphorylate protein substrates is not known. Here we provide crystallographic, biophysical and biochemical evidence demonstrating that the phosphorylated kinase domains of IR and IGF1R form a specific dimeric arrangement involving an exchange of the juxtamembrane region proximal to the kinase domain. In this dimer, the active position of α-helix C in the kinase N lobe is stabilized, which promotes downstream substrate phosphorylation. These studies afford a novel strategy for the design of small-molecule IR agonists as potential therapeutic agents for type 2 diabetes.

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Insulin Receptor (IR) and Insulin‐like growth factor 1 Receptor (IGF‐1R) are receptor tyrosine kinases (RTKs) ubiquitously distributed in human tissues. They are pre‐formed disulfide‐linked αβ homodimers. Binding of Insulin/IGF1 binding to the receptor ectodomain induces a conformational change in the quaternary structure of the receptors, which transforms the receptors from a basal state, in which trans‐phosphorylation on tyrosine residues is limited, to a trans‐phosphorylation‐competent state, and subsequently to a fully activated phosphorylated state, which stimulates catalytic activity and creates recruitment sites for downstream signaling proteins. The spatial relationships between the two kinase domains prior to and after transautophosphorylation are not known. In this study, we provide crystallographic, biophysical, and biochemical evidence demonstrating that, upon phosphorylation, the tyrosine kinase domains of IR and IGF1R form an activated kinase dimer.

https://ericlemmon.net Disciplinary background A. Music Composition Disciplinary background B. Critical Studies in Music Technology and Political Theory