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SUMMARY:Cryo-EM Forum: The structure of human thyroglobulin - Francesca Co
 scia\, MRC Laboratory of Molecular Biology\, Cambridge\, UK
DTSTART:20191108T110000Z
DTEND:20191108T120000Z
UID:TALK134458@talks.cam.ac.uk
CONTACT:Andrzej Szewczak-Harris
DESCRIPTION:Thyroglobulin is the protein precursor of thyroid hormones\, w
 hich are essential for growth\, development and control of metabolism in v
 ertebrates. Hormone synthesis from thyroglobulin (TG) occurs in the thyroi
 d gland via the iodination and coupling of pairs of tyrosines and is compl
 eted by TG proteolysis. Tyrosine proximity within TG is thought to enable 
 the coupling reaction but hormonogenic tyrosines have not been clearly ide
 ntified and the lack of a three-dimensional structure of TG has prevented 
 mechanistic understanding. Here we present the de novo structure of full-l
 ength human thyroglobulin at ~3.5 Å resolution determined by electron cry
 omicroscopy (cryo-EM). We identified all hormonogenic tyrosine pairs in th
 e structure and verified them via site-directed mutagenesis and in vitro h
 ormone production assays using human TG expressed in HEK cells. Analysis r
 evealed that proximity\, flexibility and solvent exposure of the tyrosines
  are the key characteristics of hormonogenic sites. To support the validit
 y of our insights\, we transferred the reaction site properties from TG to
  an engineered tyrosine donor-acceptor pair in the unrelated bacterial mal
 tose binding protein (MBP). This yielded hormone production with efficienc
 y comparable to TG. This structure provides an essential framework to furt
 her understand the production and regulation of thyroid hormones.
LOCATION:Department of Biochemistry\, Sanger Building\, Thomas Lecture The
 atre
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