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(Received for publication, November 2, 1995, and in revised form, June 26, 1996)
From the Fox Chase Cancer Center, Philadelphia, Pennsylvania
19111
The human serine/threonine protein kinases, Mst1
and Mst2, share considerable homology to Ste20 and p21-activated kinase
(Pak) throughout their catalytic domains. However, outside the
catalytic domains there are no significant homologies to previously
described Ste20-like kinases or other proteins. To understand the role
of the nonhomologous regions, we performed a structure/function
analysis of Mst1. A series of COOH-terminal and internal deletions
indicates that there is an element within a central 63-amino acid
region of the molecule that inhibits kinase activity. Removal of this
domain increases kinase activity approximately 9-fold.
Coimmunoprecipitation assays, the yeast two-hybrid procedure, and
in vitro cross-linking analysis indicate that Mst1
homodimerizes and that the extreme COOH-terminal 57 amino acids are
required for self-association. Size exclusion chromatography indicates
that Mst1 is associated with a high molecular weight complex in cells,
suggesting that other proteins may also oligomerize with this kinase.
While loss of dimerization alone does not affect kinase activity, a
molecule lacking both the dimerization and inhibitory domains is not as
active as one which lacks only the inhibitory domain. Comparison of
Mst1 and Mst2 indicates that both functional domains lie in regions
conserved between the two molecules.
Volume 271, Number 35,
Issue of August 30, 1996
pp. 21049-21053
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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