25,224 research outputs found
Tertiary Alphabet for the Observable Protein Structural Universe
Here, we systematically decompose the known protein structural universe into its basic elements, which we dub tertiary structural motifs (TERMs). A TERM is a compact backbone fragment that captures the secondary, tertiary, and quaternary environments around a given residue, comprising one or more disjoint segments (three on average). We seek the set of universal TERMs that capture all structure in the Protein Data Bank (PDB), finding remarkable degeneracy. Only ∼600 TERMs are sufficient to describe 50% of the PDB at sub-Angstrom resolution. However, more rare geometries also exist, and the overall structural coverage grows logarithmically with the number of TERMs. We go on to show that universal TERMs provide an effective mapping between sequence and structure. We demonstrate that TERM-based statistics alone are sufficient to recapitulate close-to-native sequences given either NMR or X-ray backbones. Furthermore, sequence variability predicted from TERM data agrees closely with evolutionary variation. Finally, locations of TERMs in protein chains can be predicted from sequence alone based on sequence signatures emergent from TERM instances in the PDB. For multisegment motifs, this method identifies spatially adjacent fragments that are not contiguous in sequence—a major bottleneck in structure prediction. Although all TERMs recur in diverse proteins, some appear specialized for certain functions, such as interface formation, metal coordination, or even water binding. Structural biology has benefited greatly from previously observed degeneracies in structure. The decomposition of the known structural universe into a finite set of compact TERMs offers exciting opportunities toward better understanding, design, and prediction of protein structure
Conformational dynamics of the Hop1 HORMA domain reveal a common mechanism with the spindle checkpoint protein Mad2.
The HORMA domain is a highly conserved protein-protein interaction module found in eukaryotic signaling proteins including the spindle assembly checkpoint protein Mad2 and the meiotic HORMAD proteins. HORMA domain proteins interact with short 'closure motifs' in partner proteins by wrapping their C-terminal 'safety belt' region entirely around these motifs, forming topologically-closed complexes. Closure motif binding and release requires large-scale conformational changes in the HORMA domain, but such changes have only been observed in Mad2. Here, we show that Saccharomyces cerevisiae Hop1, a master regulator of meiotic recombination, possesses conformational dynamics similar to Mad2. We identify closure motifs in the Hop1 binding partner Red1 and in Hop1 itself, revealing that HORMA domain-closure motif interactions underlie both Hop1's initial recruitment to the chromosome axis and its self-assembly on the axis. We further show that Hop1 adopts two distinct folded states in solution, one corresponding to the previously-observed 'closed' conformation, and a second more extended state in which the safety belt region has disengaged from the HORMA domain core. These data reveal strong mechanistic similarities between meiotic HORMADs and Mad2, and provide a mechanistic basis for understanding both meiotic chromosome axis assembly and its remodeling by the AAA+ ATPase Pch2/TRIP13
Calmodulin in Complex with Proteins and Small Molecule Ligands: Operating with the Element of Surprise. Implications for Structure-Based Drug Design
Calmodulin plays a role in several life processes, its flexibility allows binding of a number of different ligands from small molecules to amphiphilic peptide helices and proteins. Through the diversity of its functions, it is quite difficult to find new drugs, which bind to calmodulin as a target. We present available structural information on the protein, obtained by X-ray diffraction, nuclear magnetic resonance spectroscopy and molecular modeling and try to derive some conclusions on structureactivity
relationships
Elastic properties of proteins: insight on the folding process and evolutionary selection of native structures
We carry out a theoretical study of the vibrational and relaxation properties
of naturally-occurring proteins with the purpose of characterizing both the
folding and equilibrium thermodynamics. By means of a suitable model we provide
a full characterization of the spectrum and eigenmodes of vibration at various
temperatures by merely exploiting the knowledge of the protein native
structure. It is shown that the rate at which perturbations decay at the
folding transition correlates well with experimental folding rates. This
validation is carried out on a list of about 30 two-state folders. Furthermore,
the qualitative analysis of residues mean square displacements (shown to
accurately reproduce crystallographic data) provides a reliable and
statistically accurate method to identify crucial folding sites/contacts. This
novel strategy is validated against clinical data for HIV-1 Protease. Finally,
we compare the spectra and eigenmodes of vibration of natural proteins against
randomly-generated compact structures and regular random graphs. The comparison
reveals a distinctive enhanced flexibility of natural structures accompanied by
slow relaxation times at the folding temperature. The fact that these
properties are intimately connected to the presence and assembly of secondary
motifs hints at the special criteria adopted by evolution in the selection of
viable folds.Comment: Revtex 17 pages, 13 eps figure
Are Protein Folds Atypical?
Protein structures are a very special class among all possible structures. It
was suggested that a ``designability principle'' plays a crucial role in
nature's selection of protein sequences and structures. Here we provide a
theoretical base for such a selection principle, using a novel formulation of
the protein folding problem based on hydrophobic interactions. A structure is
reduced to a string of 0's and 1's which represent the surface and core sites,
respectively, as the backbone is traced. Each structure is therefore associated
with one point in a high dimensional space. Sequences are represented by
strings of their hydrophobicities and thus can be mapped into the same space. A
sequence which lies closer to a particular structure in this space than to any
other structures will have that structure as its ground state. Atypical
structures, namely those far away from other structures in the high dimensional
space, have more sequences which fold into them, and are thermodynamically more
stable. We argue that the most common folds of proteins are the most atypical
in the space of possible structures.Comment: 15 pages, 5 figure
Structural Dynamics of Free Proteins in Diffraction
Among the macromolecular patterns of biological significance, right-handed α-helices are perhaps the most abundant structural motifs. Here, guided by experimental findings, we discuss both ultrafast initial steps and longer-time-scale structural dynamics of helix-coil
transitions induced by a range of temperature jumps in large, isolated macromolecular ensembles of an α-helical protein segment thymosin β_9 (Tβ_9), and elucidate the comprehensive picture of (un)folding. In continuation of an earlier theoretical work from this laboratory that utilized a simplistic structure-scrambling algorithm combined
with a variety of self-avoidance thresholds to approximately model helix-coil transitions in Tβ_9, in the present contribution we focus on the actual dynamics of unfolding as obtained from massively distributed ensemble-convergent MD simulations which provide an unprecedented scope of information on the nature of transient macromolecular structures, and with atomic-scale spatiotemporal resolution. In addition to the use of radial distribution functions of ultrafast electron diffraction (UED) simulations in gaining an insight into the elementary steps of conformational interconversions, we also investigate the structural dynamics of the protein via
the native (α-helical) hydrogen bonding contact metric which is an intuitive coarse graining approach. Importantly, the decay of α-helical motifs and the (globular) conformational annealing in Tβ_9 occur consecutively or competitively, depending on the
magnitude of temperature jump
Self-organization of intrinsically disordered proteins with folded N-termini
Thousands of human proteins lack recognizable tertiary structure in most of their chains. Here we hypothesize that some use their structured N-terminal domains (SNTDs) to organise the remaining protein chain via intramolecular interactions, generating partially structured proteins. This model has several attractive features: as protein chains emerge, SNTDs form spontaneously and serve as nucleation points, creating more compact shapes. This reduces the risk of protein degradation or aggregation. Moreover, an interspersed pattern of SNTD-docked regions and free loops can coordinate assembly of sub-complexes in defined loop-sections and enables novel regulatory mechanisms, for example through posttranslational modifications of docked regions
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