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Vol. 12, Issue 9, 2894-2905, September 2001
Center for Basic Research in Digestive Diseases and Department of
Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
55905
Dynamins are large GTPases with mechanochemical properties that are
known to constrict and tubulate membranes. A recently identified
mammalian dynamin-like protein (DLP1) is essential for the proper
cellular distribution of mitochondria and the endoplasmic reticulum in
cultured cells. In this study, we investigated the ability of DLP1 to
remodel membranes similar to conventional dynamin. We found that the
expression of a GTPase-defective mutant, DLP1-K38A, in cultured cells
led to the formation of large cytoplasmic aggregates. Electron
microscopy (EM) of cells expressing DLP1-K38A revealed that these
aggregates were comprised of membrane tubules of a consistent diameter.
High-magnification EM revealed the presence of many regular striations
along individual membrane tubules, and immunogold labeling confirmed
the association of DLP1 with these structures. Biochemical experiments
with the use of recombinant DLP1 and labeled GTP demonstrated that
DLP1-K38A binds but does not hydrolyze or release GTP. Furthermore, the
affinity of DLP1-K38A for membrane is increased compared with wild-type
DLP1. To test whether DLP1 could tubulate membrane in vitro,
recombinant DLP1 was combined with synthetic liposomes and nucleotides.
We found that DLP1 protein alone assembled into sedimentable
macromolecular structures in the presence of
guanosine-5'-O-(3-thio)triphosphate (GTP
S) but not
GTP. EM of the GTPS-treated DLP1 revealed clusters of stacked
helical ring structures. When liposomes were included with DLP1,
formation of long membrane tubules similar in size to those formed in
vivo was observed. Addition of GTPS greatly enhanced membrane tubule
formation, suggesting the GTP-bound form of DLP1 deforms liposomes into
tubules as the DLP1-K38A does in vivo. These results provide the first
evidence that the dynamin family member, DLP1, is able to tubulate
membranes both in living cells and in vitro. Furthermore, these
findings also indicate that despite the limited homology to
conventional dynamins (35%) these proteins remodel membranes in a
similar manner.
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