14,872 research outputs found
Detecting Repetitions and Periodicities in Proteins by Tiling the Structural Space
The notion of energy landscapes provides conceptual tools for understanding
the complexities of protein folding and function. Energy Landscape Theory
indicates that it is much easier to find sequences that satisfy the "Principle
of Minimal Frustration" when the folded structure is symmetric (Wolynes, P. G.
Symmetry and the Energy Landscapes of Biomolecules. Proc. Natl. Acad. Sci.
U.S.A. 1996, 93, 14249-14255). Similarly, repeats and structural mosaics may be
fundamentally related to landscapes with multiple embedded funnels. Here we
present analytical tools to detect and compare structural repetitions in
protein molecules. By an exhaustive analysis of the distribution of structural
repeats using a robust metric we define those portions of a protein molecule
that best describe the overall structure as a tessellation of basic units. The
patterns produced by such tessellations provide intuitive representations of
the repeating regions and their association towards higher order arrangements.
We find that some protein architectures can be described as nearly periodic,
while in others clear separations between repetitions exist. Since the method
is independent of amino acid sequence information we can identify structural
units that can be encoded by a variety of distinct amino acid sequences
Functional Diversity and Structural Disorder in the Human Ubiquitination Pathway
The ubiquitin-proteasome system plays a central role in cellular regulation and protein quality control (PQC). The system is built as a pyramid of increasing complexity, with two E1 (ubiquitin activating), few dozen E2 (ubiquitin conjugating) and several hundred E3 (ubiquitin ligase) enzymes. By collecting and analyzing E3 sequences from the KEGG BRITE database and literature, we assembled a coherent dataset of 563 human E3s and analyzed their various physical features. We found an increase in structural disorder of the system with multiple disorder predictors (IUPred - E1: 5.97%, E2: 17.74%, E3: 20.03%). E3s that can bind E2 and substrate simultaneously (single subunit E3, ssE3) have significantly higher disorder (22.98%) than E3s in which E2 binding (multi RING-finger, mRF, 0.62%), scaffolding (6.01%) and substrate binding (adaptor/substrate recognition subunits, 17.33%) functions are separated. In ssE3s, the disorder was localized in the substrate/adaptor binding domains, whereas the E2-binding RING/HECT-domains were structured. To demonstrate the involvement of disorder in E3 function, we applied normal modes and molecular dynamics analyses to show how a disordered and highly flexible linker in human CBL (an E3 that acts as a regulator of several tyrosine kinase-mediated signalling pathways) facilitates long-range conformational changes bringing substrate and E2-binding domains towards each other and thus assisting in ubiquitin transfer. E3s with multiple interaction partners (as evidenced by data in STRING) also possess elevated levels of disorder (hubs, 22.90% vs. non-hubs, 18.36%). Furthermore, a search in PDB uncovered 21 distinct human E3 interactions, in 7 of which the disordered region of E3s undergoes induced folding (or mutual induced folding) in the presence of the partner. In conclusion, our data highlights the primary role of structural disorder in the functions of E3 ligases that manifests itself in the substrate/adaptor binding functions as well as the mechanism of ubiquitin transfer by long-range conformational transitions. © 2013 Bhowmick et al
Propensity to form amyloid fibrils is encoded as excitations in the free energy landscape of monomeric proteins
Protein aggregation, linked to many of diseases, is initiated when monomers
access rogue conformations that are poised to form amyloid fibrils. We show,
using simulations of src SH3 domain, that mechanical force enhances the
population of the aggregation prone () states, which are rarely populated
under force free native conditions, but are encoded in the spectrum of native
fluctuations. The folding phase diagrams of SH3 as a function of denaturant
concentration (), mechanical force (), and temperature exhibit an
apparent two-state behavior, without revealing the presence of the elusive
states. Interestingly, the phase boundaries separating the folded and
unfolded states at all [C] and fall on a master curve, which can can be
quantitatively described using an analogy to superconductors in a magnetic
field. The free energy profiles as a function of the molecular extension (),
which are accessible in pulling experiments, (), reveal the presence of a
native-like with a disordered solvent-exposed amino terminal
-strand. The structure of the state is identical to that found in
Fyn SH3 by NMR dispersion experiments. We show that the time scale for fibril
formation can be estimated from the population of the state, determined
by the free energy gap separating the native structure and the state, a
finding that can be used to assess fibril forming tendencies of proteins. The
structures of the state are used to show that oligomer formation and
likely route to fibrils occur by a domain-swap mechanism in SH3 domain.Comment: 12 pages, 8 figures, 9 supplementary figures (on 5 more pages), 2
supplementary movies (on youtube
Towards Understanding the Origin of Genetic Languages
Molecular biology is a nanotechnology that works--it has worked for billions
of years and in an amazing variety of circumstances. At its core is a system
for acquiring, processing and communicating information that is universal, from
viruses and bacteria to human beings. Advances in genetics and experience in
designing computers have taken us to a stage where we can understand the
optimisation principles at the root of this system, from the availability of
basic building blocks to the execution of tasks. The languages of DNA and
proteins are argued to be the optimal solutions to the information processing
tasks they carry out. The analysis also suggests simpler predecessors to these
languages, and provides fascinating clues about their origin. Obviously, a
comprehensive unraveling of the puzzle of life would have a lot to say about
what we may design or convert ourselves into.Comment: (v1) 33 pages, contributed chapter to "Quantum Aspects of Life",
edited by D. Abbott, P. Davies and A. Pati, (v2) published version with some
editin
Capturing coevolutionary signals in repeat proteins
The analysis of correlations of amino acid occurrences in globular proteins
has led to the development of statistical tools that can identify native
contacts -- portions of the chains that come to close distance in folded
structural ensembles. Here we introduce a statistical coupling analysis for
repeat proteins -- natural systems for which the identification of domains
remains challenging. We show that the inherent translational symmetry of repeat
protein sequences introduces a strong bias in the pair correlations at
precisely the length scale of the repeat-unit. Equalizing for this bias reveals
true co-evolutionary signals from which local native-contacts can be
identified. Importantly, parameter values obtained for all other interactions
are not significantly affected by the equalization. We quantify the robustness
of the procedure and assign confidence levels to the interactions, identifying
the minimum number of sequences needed to extract evolutionary information in
several repeat protein families. The overall procedure can be used to
reconstruct the interactions at long distances, identifying the characteristics
of the strongest couplings in each family, and can be applied to any system
that appears translationally symmetric
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