Molecular recognition of thyroglobulin by sortilin.

Area of Science:

• Molecular Biology
• Structural Biology
• Cell Biology

Background:

• Sortilin is a membrane receptor involved in protein cargo trafficking.
• In the thyroid, sortilin mediates thyroglobulin (TG) endocytosis, crucial for thyroid homeostasis.
• The molecular basis for sortilin's recognition of TG, particularly its proposed preference for iodinated forms, remains unclear.

Purpose of the Study:

• To elucidate the molecular details of the interaction between sortilin and thyroglobulin (TG).
• To determine the structural basis for sortilin-TG binding.
• To investigate the role of TG iodination and oligomeric state in sortilin recognition.

Main Methods:

• Integrative structural biology approaches.
• AlphaPulldown assay.
• Sequence analysis.

Main Results:

• Sortilin binds to an unstructured C-terminal peptide of TG.
• Sortilin shows a preference for monomeric TG over dimeric TG.
• The interaction is independent of TG iodination state, relying on monomerization.
• Other sortilin ligands likely share similar unstructured peptide recognition motifs.

Conclusions:

• The study reveals the specific binding interface between sortilin and TG.
• Sortilin recognizes monomeric TG through an unstructured peptide motif.
• This mechanism provides insights into how sortilin recognizes various protein cargoes.
• The findings challenge the previous hypothesis regarding iodination-dependent TG recognition by sortilin.