PXD014821

PXD014821 is an original dataset announced via ProteomeXchange.

Title	The structure of human thyroglobulin
Description	Thyroglobulin protein is the precursor of thyroid hormones, which are essential for growth, development and control of metabolism in vertebrates. Hormone synthesis from thyroglobulin (TG) occurs in the thyroid gland via the iodination and subsequent coupling of pairs of tyrosine amino acids, whose positions in TG have not been clearly identified. Tyrosine proximity within TG is thought to enable the coupling reactions but the lack of a three-dimensional structure of TG has prevented mechanistic understanding. Here we determined the structure of full-length human thyroglobulin at ~3.4 Å resolution by cryo-electron microscopy (cryo-EM). To enable perturbation experiments we expressed human TG in human HEK cells and showed it to be active in hormone production. We identified all hormogenic tyrosine pairs in the structure and verified them via site-directed mutagenesis and in vitro hormone production assays. Analysis revealed that proximity, flexibility and solvent exposure of the tyrosines are key characteristics of the hormogenic sites. To support the validity of our insights, we engineered the small bacterial protein MBP (maltose binding protein) to produce thyroid hormones with similar efficiency as TG. Finally, our study provides an essential framework to further understand the production and regulation of thyroid hormones, including in thyroid diseases.
HostingRepository	PRIDE
AnnounceDate	2020-02-06
AnnouncementXML	Submission_2020-03-24_00:05:25.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD014821
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Ludwig Sinn
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	Deamidated; Oxidation; Carbamidomethyl
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2019-07-30 02:33:43	ID requested
1	2020-02-06 04:17:29	announced
⏵ 2	2020-03-24 00:05:26	announced	2020-03-24: Updated publication reference for PubMed record(s): 32025030.

Coscia F, Taler-Ver, č, i, č A, Chang VT, Sinn L, O'Reilly FJ, Izor, é T, Renko M, Berger I, Rappsilber J, Turk D, L, ö, we J, The structure of human thyroglobulin. Nature, 578(7796):627-630(2020) [pubmed]

submitter keyword: thyroxine

T3

T4

thyroid hormone

tyrosine iodination

cryo-EM

Juri Rappsilber, PhD
contact affiliation	Bioanalytics, Institute of Biotechnology, Technische Universität Berlin, 13355 Berlin, Germany. Wellcome Center for Cell Biology, University of Edinburgh, Edinburgh, EH9 3BF, United Kingdom.
contact email	juri.rappsilber@tu-berlin.de
lab head
Ludwig Sinn
contact affiliation	TU Berlin, Bioanalytics, J. Rappsilber PhD
contact email	l.sinn@tu-berlin.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD014821
     1. Label: PRIDE project
     2. Name: The structure of human thyroglobulin