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A chaperone cascade sorts proteins for posttranslational membrane insertion into the endoplasmic reticulum
Fei Wang1, Emily C Brown, Gary Mak
1Department of Molecular and Cellular Biology, Harvard University, Northwest Labs, Cambridge, MA 02138, USA.
Molecular Cell
|September 21, 2010
Summary
Scientists discovered a protein complex that sorts tail-anchored (TA) proteins to either the ER or mitochondria. This complex, the TMD recognition complex (TRC), ensures correct membrane insertion by recognizing specific signals on TA proteins.
Area of Science:
- Cell Biology
- Molecular Biology
- Protein Trafficking
Background:
- Tail-anchored (TA) proteins are crucial for cellular functions, inserting post-translationally into the endoplasmic reticulum (ER) or mitochondrial outer membrane.
- The C-terminal transmembrane domains (TMDs) of TA proteins dictate their membrane destination, but the mechanisms of signal recognition and sorting are not fully understood.
Purpose of the Study:
- To elucidate the composition and function of the protein complex responsible for recognizing and sorting TA proteins.
- To understand how distinct targeting signals within TA protein TMDs are differentiated for proper membrane insertion.
Main Methods:
- Identification and characterization of a conserved multiprotein complex involved in TA protein sorting.
- Biochemical reconstitution experiments using purified components.
- Genetic manipulation of mitochondrial TA protein TMDs to alter TRC subunit recognition.
Main Results:
- A conserved multiprotein TMD recognition complex (TRC) was identified, with distinct subunits recognizing ER-specific versus mitochondrial-specific TMD signals.
- Mutagenesis of a mitochondrial TMD switched its TRC recognition, leading to ER misinsertion.
- Biochemical reconstitution demonstrated that TRC tethers and activates Get3, facilitating the selective transfer of ER-bound TA proteins to Get3.
Conclusions:
- The TRC acts as the initial sorting machinery for TA proteins, distinguishing between ER and mitochondrial targeting signals.
- ER-bound TA proteins are channeled through a TMD chaperone cascade initiated by TRC, culminating in Get3-TA protein complex formation for ER insertion.
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