Biophysics of Signal Transduction
Signal
transduction networks are key processes utilized by organisms to sense their
environment and to regulate essentially all life processes such as their
metabolism, motility, reproduction, etc. Physically, signal transduction
proceeds via local initial changes upon stimulation – e.g. light absorption or
ligand binding followed by elementary events such as electron transfer,
hydrogen-bond rearrangement, isomerization. In turn, the Van der Waals
complementarities that thus far defined the protein’s conformation are
disturbed, leading to larger-scale movements of the protein and, ultimately in
changes of affinity of interacting signaling proteins. Over the last years I
have developed a research program at the VU laser center to unravel the
molecular mechanisms of light-driven signal transduction. The goal of the
program is to understand the dynamic-structural basis of signal transduction at
the molecular level, from initiation by a flash of light to propagation of
information-encoding structural changes in the signaling proteins, to
organismal output. To this end, advanced time-resolved spectroscopic techniques
such as ultrafast transient absorption, ultrafast IR and Raman, time-resolved FTIR
and multi-pulse spectroscopy are employed.
Signal
transduction proteins and networks have a strictly modular architecture with
conserved input and output domains. Light-driven signaling proteins and
networks often are similar to those that have quite different input signals
(such as oxygen, temperature, food sources, metabolites etc.) and are eminently
suited for biophysical studies since they can be activated by a short laser
flash. The model systems of the program are mainly bacterial in origin and
chosen in such a way that knowledge with a high degree of general significance
is obtained. By studying the intact photo-activated signal transduction
proteins at increasing levels of complexity, to culminate in light-driven
signal transduction studies in whole cells, the research is firmly placed in a
Systems Biology context. Moreover, the light-sensitive input domains are
photochromic and photoreversible (i.e., they can be turned ‘on’ and ‘off’ by
laser flashes of different color) which offers unprecedented control over
signal transduction pathways by means of multi-pulse control spectroscopies.
The
program carries a considerable significance for the society at large. The
bacterial model signaling proteins and networks of the program have many homologues
in human pathogens. The latter form a prime target for the development of new
generations of antibiotics, which are dearly needed in the face of ever
increasing resistance to existing ones. Likewise, several forms of cancer are
caused by disturbances in human signaling pathways analogous to those under
investigation in the program, and may be cured by intervention at the molecular
level.
Presently the program is supported by grants from NWO-ALW: a VIDI grant
to myself (600 kEur), the Molecule to Cell program (500 kEur, with R. van
Grondelle and K.J. Hellingwerf) and an investment grant to construct an
advanced multi-pulse spectrometer (672 kEur, with R. van Grondelle). Close collaborations exist with
prof. Klaas Hellingwerf at SILS/UvA, with prof. Sean Crosson at the
Key
publications
J.T.M. Kennis and S. Crosson
A bacterial pathogen sees the light
Science 317, 2007, p. 1041-1042 (Perspective)
M.T.A. Alexandre, J.C. Arents, R. van Grondelle, K.J. Hellingwerf, J.T.M. Kennis
A base-catalyzed mechanism for dark
state recovery in the Avena sativa phototropin-1 LOV2 domain
Biochemistry, 46, 2007, p. 3129-3137
M. Gauden, J.S Grinstead, W. Laan, I.H.M. van Stokkum, M. Avila-Perez,
K.C. Toh, R. Boelens, R. Kaptein, R. van Grondelle, K.J. Hellingwerf,
J.T.M. Kennis
On the role of aromatic side chains in the photoactivation of BLUF domains
Biochemistry 46, 2007, p. 7405-7415
M. Gauden,
I.H.M. van Stokkum, J.M. Key, D. Ch. Luhrs, R. van
Grondelle, P. Hegemann, J.T.M. Kennis, Hydrogen
bond switching via a radical pair mechanism in a flavin-binding photoreceptor
Proc. Natl. Acad. Sci. USA 103, 2006,
p. 10895-10900
J. Am. Chem. Soc. 126, 2004, p.
4512-4513