title: Assembly of immunoglobulin light chains as a prerequisite for secretion. A model for oligomerization-dependent subunit folding.
abstract: Oligomeric proteins usually have to assemble into their final quartenary structure to be secreted. However, most immunoglobulin (Ig) light (L) chains can be exported as free chains, whereas only a few Ig L chains, here referred to as export-incompetent, have to assemble with Ig heavy (H) chains into antibody molecules to be secreted. In the absence of Ig H chain expression, these export-incompetent Ig L chains remain bound to BiP as partially folded monomers with only one of the two internal disulfide bonds being formed. To understand the apparent discrepancy in Ig L chain export, we performed assembly studies with chimeric Ig chains and found that the variable (V) domain of the export-incompetent NS1 kappa chain cannot mediate homodimer formation. Conversely, the V domain of the export-competent J558L lambda1 chain supports homodimer formation and, concordantly, these Ig L chains are secreted as noncovalently or covalently linked homodimers. We show that the export-incompetent mutant lambda1 FS62 chain forms disulfide bonds in both domains only upon pairing with Ig H chain and is secreted as part of an antibody. Therefore, Ig L chain assembly seems to be a prerequisite for complete folding, indicating that Ig L chain secretion generally depends on either homo- or heterodimer formation. We discuss a mechanism that controls oligomerization by monitoring the conformation of individual subunits that cannot proceed in folding prior to successful assembly.
authors.affiliation: Institut für Biochemie I der Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Leitzgen
authors.forename: M R
authors.initials: MR
authors.lastname: Knittler
authors.forename: I G
authors.initials: IG
authors.lastname: Haas
mesh_terms: D000818:Animals; D002460:Cell Line; D019281:Dimerization; D015321:Gene Rearrangement; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D007147:Immunoglobulin Light Chains / Q000096:biosynthesis / Q000737:chemistry* / Q000378:metabolism*; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D007145:Immunoglobulin kappa-Chains / Q000737:chemistry / Q000378:metabolism; D007146:Immunoglobulin lambda-Chains / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D011487:Protein Conformation; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins