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Vol. 9, Issue 4, 853-863, April 1998
Department of Physiology and Biophysics, University of Texas
Medical Branch, Galveston, Texas 77555-0641
The membrane assembly of polytopic membrane proteins is a
complicated process. Using Chinese hamster P-glycoprotein (Pgp) as a
model protein, we investigated this process previously and found that
Pgp expresses more than one topology. One of the variations occurs at
the transmembrane (TM) domain including TM3 and TM4: TM4 inserts into
membranes in an Nin-Cout rather than the
predicted Nout-Cin orientation, and TM3 is in
cytoplasm rather than the predicted Nin-Cout
orientation in the membrane. It is possible that TM4 has a strong
activity to initiate the Nin-Cout membrane insertion, leaving TM3 out of the membrane. Here, we tested this hypothesis by expressing TM3 and TM4 in isolated conditions. Our results show that TM3 of Pgp does not have de novo
Nin-Cout membrane insertion activity whereas
TM4 initiates the Nin-Cout membrane insertion
regardless of the presence of TM3. In contrast, TM3 and TM4 of another
polytopic membrane protein, cystic fibrosis transmembrane conductance
regulator (CFTR), have a similar level of de novo
Nin-Cout membrane insertion activity and TM4 of
CFTR functions only as a stop-transfer sequence in the presence of TM3.
Based on these findings, we propose that 1) the membrane insertion of
TM3 and TM4 of Pgp does not follow the sequential model, which predicts
that TM3 initiates Nin-Cout membrane insertion whereas TM4 stops the insertion event; and 2) "leaving one TM segment
out of the membrane" may be an important folding mechanism for
polytopic membrane proteins, and it is regulated by the
Nin-Cout membrane insertion activities of the
TM segments.
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