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Mechano-transduction: from molecules to tissues.
External forces play complex roles in cell organization, fate, and homeostasis. Changes in these forces, or how cells respond to them, can result in abnormal embryonic development and diseases in adults. How cells sense and respond to these mechanical stimuli requires an understanding of the biophysical principles that underlie changes in protein conformation and result in alterations in the organization and function of cells and tissues. Here, we discuss mechano-transduction as it applies to protein conformation, cellular organization, and multi-cell (tissue) function
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p97 Disease Mutations Modulate Nucleotide-Induced Conformation to Alter Protein-Protein Interactions.
The AAA+ ATPase p97/VCP adopts at least three conformations that depend on the binding of ADP and ATP and alter the orientation of the N-terminal protein-protein interaction (PPI) domain into up and down conformations. Point mutations that cause multisystem proteinopathy 1 (MSP1) are found at the interface of the N domain and D1-ATPase domain and potentially alter the conformational preferences of p97. Additionally, binding of adaptor proteins to the N-domain regulates p97s catalytic activity. We propose that p97/adaptor PPIs are coupled to p97 conformational states. We evaluated the binding of nucleotides and the adaptor proteins p37 and p47 to wild-type p97 and MSP1 mutants. Notably, p47 and p37 bind 8-fold more weakly to the ADP-bound conformation of wild-type p97 compared to the ATP-bound conformation. However, MSP1 mutants lose this nucleotide-induced conformational coupling because they destabilize the ADP-bound, down conformation of the N-domain. Loss in conformation coupling to PPIs could contribute to the mechanism of MSP1
Mobility Measurements Probe Conformational Changes in Membrane Proteins due to Tension
The function of membrane-embedded proteins such as ion channels depends
crucially on their conformation. We demonstrate how conformational changes in
asymmetric membrane proteins may be inferred from measurements of their
diffusion. Such proteins cause local deformations in the membrane, which induce
an extra hydrodynamic drag on the protein. Using membrane tension to control
the magnitude of the deformations and hence the drag, measurements of
diffusivity can be used to infer--- via an elastic model of the protein--- how
conformation is changed by tension. Motivated by recent experimental results
[Quemeneur et al., Proc. Natl. Acad. Sci. USA, 111 5083 (2014)] we focus on
KvAP, a voltage-gated potassium channel. The conformation of KvAP is found to
change considerably due to tension, with its `walls', where the protein meets
the membrane, undergoing significant angular strains. The torsional stiffness
is determined to be 26.8 kT at room temperature. This has implications for both
the structure and function of such proteins in the environment of a
tension-bearing membrane.Comment: Manuscript: 4 pages, 4 figures. Supplementary Material: 8 pages, 1
figur
Conformational Dependence of a Protein Kinase Phosphate Transfer Reaction
Atomic motions and energetics for a phosphate transfer reaction catalyzed by
the cAMP-dependent protein kinase (PKA) are calculated by plane-wave density
functional theory, starting from structures of proteins crystallized in both
the reactant conformation (RC) and the transition-state conformation (TC). In
the TC, we calculate that the reactants and products are nearly isoenergetic
with a 0.2 eV barrier; while phosphate transfer is unfavorable by over 1.2 eV
in the RC, with an even higher barrier. With the protein in the TC, the motions
involved in reaction are small, with only P and the catalytic proton
moving more than 0.5 \AA. Examination of the structures reveals that in the RC
the active site cleft is not completely closed and there is insufficient space
for the phosphorylated serine residue in the product state. Together, these
observations imply that the phosphate transfer reaction occurs rapidly and
reversibly in a particular conformation of the protein, and that the reaction
can be gated by changes of a few tenths of an \AA in the catalytic site.Comment: revtex4, 7 pages, 4 figures, to be submitted to Scienc
CLP-based protein fragment assembly
The paper investigates a novel approach, based on Constraint Logic
Programming (CLP), to predict the 3D conformation of a protein via fragments
assembly. The fragments are extracted by a preprocessor-also developed for this
work- from a database of known protein structures that clusters and classifies
the fragments according to similarity and frequency. The problem of assembling
fragments into a complete conformation is mapped to a constraint solving
problem and solved using CLP. The constraint-based model uses a medium
discretization degree Ca-side chain centroid protein model that offers
efficiency and a good approximation for space filling. The approach adapts
existing energy models to the protein representation used and applies a large
neighboring search strategy. The results shows the feasibility and efficiency
of the method. The declarative nature of the solution allows to include future
extensions, e.g., different size fragments for better accuracy.Comment: special issue dedicated to ICLP 201
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