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J Biol Chem, Vol. 274, Issue 3, 1423-1431, January 15, 1999
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From the Departments of Ha-Ras undergoes post-translational modifications
(including attachment of farnesyl and palmitate) that culminate in
localization of the protein to the plasma membrane. Because palmitate
is not attached without prior farnesyl addition, the distinct
contributions of the two lipid modifications to membrane attachment or
biological activity have been difficult to examine. To test if
palmitate is able to support these crucial functions on its own, novel
C-terminal mutants of Ha-Ras were constructed, retaining the natural
sites for palmitoylation, but replacing the C-terminal residue of the CAAX signal for prenylation with six lysines. Both the
Ext61L and ExtWT proteins were modified in a dynamic fashion by
palmitate, without being farnesylated; bound to membranes modestly
(40% as well as native Ha-Ras); and retained appropriate GTP binding
properties. Ext61L caused potent transformation of NIH 3T3 cells and,
unexpectedly, an exaggerated differentiation of PC12 cells. Ext61L with
the six lysines but lacking palmitates was inactive. Thus, farnesyl is
not needed as a signal for palmitate attachment or removal, and a
combination of transient palmitate modification and basic residues can
support Ha-Ras membrane binding and two quite different biological
functions. The roles of palmitate can therefore be independent of and
distinct from those of farnesyl. Reciprocally, if membrane association
can be sustained largely through palmitates, farnesyl is freed to
interact with other proteins.
Biochemistry and
§ Zoology and Genetics, Iowa State University, Ames, Iowa
50011 and the ¶ Department of Pharmacology, University of North
Carolina, Chapel Hill, North Carolina 27599
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