Dimerization-dependent Folding Underlies Assembly Control of the Clonotypic {alpha}{beta}T cell Receptor Chains [Protein Structure and Folding]

September 23rd, 2015 by Feige, M. J., Behnke, J., Mittag, T., Hendershot, L. M.

In eukaryotic cells, secretory pathway proteins must pass stringent quality control checkpoints before exiting the endoplasmic reticulum (ER). Acquisition of native structure is generally considered to be the most important prerequisite for ER exit. However, structurally detailed protein folding studies in the ER are few. Furthermore, aberrant ER quality control (ERQC) decisions are associated with a large and increasing number of human diseases, highlighting the need for more detailed studies on the molecular determinants that result in proteins being either secreted or retained. Here, we used the clonotypic αβ chains of the T cell receptor (TCR) as a model to analyze lumenal determinants of ERQC with a particular emphasis on how proper assembly of oligomeric proteins can be monitored in the ER. A combination of in vitro and in vivo approaches allowed us to provide a detailed model for αβTCR assembly control in the cell. We found that folding of the TCR α-chain constant domain Cα is dependent on αβ-heterodimerization. Furthermore, our data show that some variable regions associated with either chain can remain incompletely folded until chain pairing occurs. Together, these data argue for template-assisted folding at more than one point in the TCR α/β assembly process that allows specific recognition of unassembled clonotypic chains by the ER chaperone machinery and thus reliable quality control of this important immune receptor. Additionally, it highlights an unreported possible limitation in the α- and β-chain combinations that will comprise the T cell repertoire.
  • Posted in Journal of Biological Chemistry, Publications
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