title: Dimerization-dependent folding underlies assembly control of the clonotypic αβT cell receptor chains.
abstract: 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 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 ER quality control 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, which allows specific recognition of unassembled clonotypic chains by the ER chaperone machinery and, therefore, reliable quality control of this important immune receptor. Additionally, it highlights an unreported possible limitation in the α and β chain combinations that comprise the T cell repertoire.
authors.affiliation: From the Departments of Tumor Cell Biology and matthias.feige@tum.de.
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Feige
authors.affiliation: From the Departments of Tumor Cell Biology and.
authors.forename: Julia
authors.initials: J
authors.lastname: Behnke
authors.affiliation: Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors.forename: Tanja
authors.initials: T
authors.lastname: Mittag
authors.affiliation: From the Departments of Tumor Cell Biology and linda.hendershot@stjude.org.
authors.forename: Linda M
authors.initials: LM
authors.lastname: Hendershot
mesh_terms: D000818:Animals; D019556:COS Cells; D037281:Calnexin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D002999:Clone Cells; D018360:Crystallography, X-Ray; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D017510:Protein Folding; D055503:Protein Multimerization; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011994:Recombinant Proteins; D037281:Calnexin
keywords: ER quality control; T cell receptor; endoplasmic reticulum (ER); membrane protein; protein assembly; protein folding