Molecular basis of the TRAP complex function in ER protein biogenesis

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• The translocon-associated protein (TRAP) complex is crucial for protein biogenesis in the endoplasmic reticulum (ER).
• It interacts with the Sec translocon and ribosome, aiding secretory and membrane protein translocation.
• TRAP is vital for the secretion of hormones like insulin.

Purpose of the Study:

• To elucidate the molecular architecture of the mammalian TRAP complex.
• To understand how TRAP engages with the translating ribosome and Sec61 translocon.
• To investigate the functional consequences of TRAP mutations on protein secretion and ER stress.

Main Methods:

• High-resolution structural analysis of the mammalian TRAP complex.
• Cryo-electron microscopy to visualize TRAP-ribosome-translocon interactions.
• Structure-guided mutagenesis in Caenorhabditis elegans to assess functional impact.

Main Results:

• The molecular architecture reveals TRAP is anchored to the ribosome by a long tether and stabilized by a loop.
• A cradle-like lumenal domain of TRAP is positioned to interact with nascent polypeptide chains.
• TRAP mutations in C. elegans caused growth deficits, ER stress, and impaired protein hormone secretion.

Conclusions:

• The study reveals the detailed molecular architecture of the TRAP complex and its interaction with the ribosome-translocon machinery.
• TRAP's structure facilitates its role in guiding nascent proteins into the ER.
• These findings provide mechanistic insights into TRAP's function in protein biogenesis and secretion, with implications for ER homeostasis.