Cysteines in CH1 underlie retention of unassembled Ig heavy chains - PubMed (original) (raw)
. 2005 Apr 15;280(15):14402-12.
doi: 10.1074/jbc.M500161200. Epub 2005 Feb 10.
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- PMID: 15705573
- DOI: 10.1074/jbc.M500161200
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Cysteines in CH1 underlie retention of unassembled Ig heavy chains
Yechiel Elkabetz et al. J Biol Chem. 2005.
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Abstract
Conformation, structure, and oligomeric state of immunoglobulins not only control quality and functional properties of antibodies but are also critical for immunoglobulins secretion. Unassembled immunoglobulin heavy chains are retained intracellularly by delayed folding of the C(H)1 domain and irreversible interaction of BiP with this domain. Here we show that the three C(H)1 cysteines play a central role in immunoglobulin folding, assembly, and secretion. Remarkably, ablating all three C(H)1 cysteines negates retention and enables BiP cycling and non-canonical folding and assembly. This phenomenon is explained by interdependent formation of intradomain and interchain disulfides, although both bonds are dispensable for secretion. Substituting Cys-195 prevents formation not only of the intradomain disulfide, but also of the interchain disulfide bond with light chain, BiP displacement, and secretion. Mutating the light chain-interacting Cys-128 hinders disulfide bonding of intradomain cysteines, allowing their opportunistic bonding with light chain, without hampering secretion. We propose that the role of C(H)1 cysteines in immunoglobulin assembly and secretion is not simply to engage in disulfide bridges, but to direct proper folding and interact with the retention machinery.
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