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Structural features of thyroglobulin linked to protein trafficking
Cintia E Citterio1,2, Kookjoo Kim3, Bhavana Rajesh1
1Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Protein Science : a Publication of the Protein Society
|September 17, 2023
Summary
Thyroglobulin folding and ER quality control were studied using bioengineered mutants. Some mutations disrupt folding and trafficking, causing hypothyroidism, while others have minimal impact.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Thyroglobulin (Tg) is essential for thyroid hormone synthesis and must navigate endoplasmic reticulum (ER) quality control.
- Defective Tg folding or trafficking can lead to hypothyroidism.
- The precise folding pathway and ER quality control mechanisms for Tg remain largely unelucidated.
Purpose of the Study:
- To investigate the impact of specific mutations on Tg folding, trafficking, and ER quality control.
- To understand how different structural elements of Tg contribute to its secretion competence.
- To identify key factors governing Tg processing within the ER.
Main Methods:
- Bioengineering of three novel classes of recombinant thyroglobulin mutants.
- Analysis of mutant Tg folding, trafficking, and ER quality control phenotypes.
- Utilizing insights from recent cryo-electron microscopy structures of thyroglobulin.
Main Results:
- Mutations in region I's disulfide bond had minimal impact on secretion competence.
- A surface mutation in the cholinesterase-like domain impaired trafficking by affecting inter-regional contacts without altering regional folding.
- A conserved disulfide in the cholinesterase-like domain significantly disrupted local and global folding, blocking Tg in the ER.
Conclusions:
- Distinct mutations differentially affect thyroglobulin ER quality control by impacting domain-specific folding, regional contacts, or both.
- These findings provide critical insights into the complex folding and trafficking pathways of thyroglobulin.
- Understanding these mechanisms is crucial for addressing thyroglobulin-related hypothyroidism.
Keywords:
contact interfacecysteinedisulfide bondendoplasmic reticulumhypothyroidismprotein traffickingregional misfoldingMore Related Videos
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