REFERENCES:
Malecka & Peterson. “Face-to-Face, Pak-to-Pak.” (2011)
Structure 19(12), pgs 1723 – 1724.
Wang et al. “Structural Insights into the Autoactivation
Mechanism of p21-Activated Protein Kinase.” (2011) Structure 19(12), pgs 1752 –
1761.
Many
kinases require the phosphorylation of a residue within their active site to
help maintain a conformation that is compatible with substrate binding/kinase
activity. While some kinases are able to
phosphorylate other kinases, many times it is the kinase itself which performs
autophosphorylation. However, it is an
interesting question: if the kinase requires phosphorylation to function but it
itself must provide the phosphorylation, how does that work? It is nearly a “chicken or the egg” problem.
In the
issue of Structure published on December 6th, two papers discuss the
de novo phosphorylation of the Pak1 (p21-activated kinase 1) protein. A commentary offered by Malecka and Peterson
discuss the history of common mutations often used by bench scientists to
achieve “kinase-dead” proteins that are useful for crystallization as well as
an overview of other kinases whose crystal structures reveal dimeric structures
where the active loop of one subunit is placed within the active site of the
other subunit. The authors discuss two
ways in which kinases can transiently adopt active conformations within the
dimer to achieve autophosphorylation in trans: symmetric and asymmetric. Symmetric structures, such as those seen for
the kinases Chk2 and Ire1, place each others activation loops in their active
sites while asymmetric structures, such as DAPK3 and IGF1R, have only one subunit place its activation loop within the active site of the other
subunit.
Pak1,
as reported by Wang et al, adopts a symmetric trans-autophosphorylation
structure. Interestingly, the authors
also report that the common lysine mutations made within the active site are not
100% kinase-dead so caution should be used when trusting them as such.
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