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Vol. 10, Issue 7, 2209-2219, July 1999
*Department of Tumor Cell Biology, St. Jude Children's Research
Hospital, Memphis, Tennessee 38105; and The immunoglobulin (Ig) molecule is composed of two identical heavy
chains and two identical light chains (H2L2).
Transport of this heteromeric complex is dependent on the correct
assembly of the component parts, which is controlled, in part, by the
association of incompletely assembled Ig heavy chains with the
endoplasmic reticulum (ER) chaperone, BiP. Although other heavy
chain-constant domains interact transiently with BiP, in the absence of
light chain synthesis, BiP binds stably to the first constant domain (CH1) of the heavy chain, causing it to be retained in the
ER. Using a simplified two-domain Ig heavy chain
(VH-CH1), we have determined why BiP remains
bound to free heavy chains and how light chains facilitate their
transport. We found that in the absence of light chain expression, the
CH1 domain neither folds nor forms its intradomain
disulfide bond and therefore remains a substrate for BiP. In vivo,
light chains are required to facilitate both the folding of the
CH1 domain and the release of BiP. In contrast, the
addition of ATP to isolated BiP-heavy chain complexes in vitro causes
the release of BiP and allows the CH1 domain to fold in the
absence of light chains. Therefore, light chains are not intrinsically
essential for CH1 domain folding, but play a critical role
in removing BiP from the CH1 domain, thereby allowing it to
fold and Ig assembly to proceed. These data suggest that the assembly
of multimeric protein complexes in the ER is not strictly dependent on
the proper folding of individual subunits; rather, assembly can drive
the complete folding of protein subunits.
Department of
Biochemistry, University of Tennessee, Memphis, Tennessee 38163
Corresponding author. E-mail
address: linda.hendershot{at}stjude.org.
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