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J. Cell Biol.,
Volume 144, Number 1, January 11, 1999 21-30
* Department of Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105; Immunoglobulin heavy chain-binding protein (BiP) is a member of the hsp70 family of chaperones and one of the most abundant proteins in the ER
lumen. It is known to interact transiently with many nascent proteins as they enter the ER and more stably with protein subunits produced in stoichiometric excess
or with mutant proteins. However, there also exists a
large number of secretory pathway proteins that do not
apparently interact with BiP. To begin to understand
what controls the likelihood that a nascent protein entering the ER will associate with BiP, we have examined the in vivo folding of a murine Laboratoire
d'Enzymologie and Centre d'Ingénierie des Protéines, Institut de Chimie B6, Université de Liège, Sart-Tilman, B-4000 Liège,
Belgium; § Argonne National Laboratories, Argonne, Illinois 60439; and ¶ Department of Biochemistry, University of Tennessee,
Memphis, Tennessee 38163
I immunoglobulin (Ig) light chain (LC). This LC is composed of two Ig
domains that can fold independent of the other and
that each possess multiple potential BiP-binding sequences. To detect BiP binding to the LC during folding, we used BiP ATPase mutants, which bind irreversibly to proteins, as "kinetic traps." Although both the
wild-type and mutant BiP clearly associated with the
unoxidized variable region domain, we were unable to
detect binding of either BiP protein to the constant region domain. A combination of in vivo and in vitro
folding studies revealed that the constant domain folds rapidly and stably even in the absence of an intradomain disulfide bond. Thus, the simple presence of a
BiP-binding site on a nascent chain does not ensure
that BiP will bind and play a role in its folding. Instead,
it appears that the rate and stability of protein folding
determines whether or not a particular site is recognized, with BiP preferentially binding to proteins that
fold slowly or somewhat unstably.
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