共查询到20条相似文献，搜索用时 15 毫秒
1.
Marco Necci Damiano Piovesan Silvio C. E. Tosatto 《Protein science : a publication of the Protein Society》2016,25(12):2164-2174
Intrinsic disorder (ID) in proteins has been extensively described for the last decade; a large‐scale classification of ID in proteins is mostly missing. Here, we provide an extensive analysis of ID in the protein universe on the UniProt database derived from sequence‐based predictions in MobiDB. Almost half the sequences contain an ID region of at least five residues. About 9% of proteins have a long ID region of over 20 residues which are more abundant in Eukaryotic organisms and most frequently cover less than 20% of the sequence. A small subset of about 67,000 (out of over 80 million) proteins is fully disordered and mostly found in Viruses. Most proteins have only one ID, with short ID evenly distributed along the sequence and long ID overrepresented in the center. The charged residue composition of Das and Pappu was used to classify ID proteins by structural propensities and corresponding functional enrichment. Swollen Coils seem to be used mainly as structural components and in biosynthesis in both Prokaryotes and Eukaryotes. In Bacteria, they are confined in the nucleoid and in Viruses provide DNA binding function. Coils & Hairpins seem to be specialized in ribosome binding and methylation activities. Globules & Tadpoles bind antigens in Eukaryotes but are involved in killing other organisms and cytolysis in Bacteria. The Undefined class is used by Bacteria to bind toxic substances and mediate transport and movement between and within organisms in Viruses. Fully disordered proteins behave similarly, but are enriched for glycine residues and extracellular structures. 相似文献
2.
The process of natural selection acts both on individual organisms within a population and on individual cells within an organism as they develop into cancer. In this work, we have taken a first step toward understanding the differences in selection pressures exerted on the human genome under these disparate circumstances. Focusing on single amino acid substitutions, we have found that cancer‐related mutations (CRMs) are frequent in evolutionarily conserved sites, whereas single amino acid polymorphisms (SAPs) tend to appear in sites having a more relaxed evolutionary pressure. Those CRMs classed as cancer driver mutations show greater enrichment for conserved sites than passenger mutations. Consistent with this, driver mutations are enriched for sites annotated as key functional residues and their neighbors, and are more likely to be located on the surface of proteins than expected by chance. Overall the pattern of CRM and polymorphism is remarkably similar, but we do see a clear signal indicative of diversifying selection for disruptive amino acid substitutions in the cancer driver mutations. The ultimate consequence of the appearance of those mutations must be advantageous for the tumor cell, leading to cell population‐growth and migration events similar to those seen in natural ecosystems. Proteins 2010. © 2009 Wiley‐Liss, Inc. 相似文献
3.
Inspection of structure changes in proteins borne by altering their sequences brings understanding of physics, functioning and evolution of existing proteins, and helps engineer modified ones. On single amino acid substitutions, the most frequent mutation type, shifts in backbone conformation are typically small, raising doubts if and how such minor modifications could drive evolutionary divergence. Here, we report that the distribution of magnitudes of structure change on such substitutions is heavy-tailed--whereas protein structures are robust to most substitutions, changes much larger than average occur with raised odds compared to what would be expected for exponential distribution with the same mean. This nonexponential behavior allows for reconciling the apparent contradiction between the observed conservation of protein structures and the substantial evolutionary plasticity implied in their diversity. The presence of the heavy tail in the distribution promotes structure divergence, facilitating exploration of new functionality, and conformations within folds, as well as exploration of structure space for new folds. 相似文献
4.
Vesicular stomatitis virus glycoprotein G (VSV‐G) belongs to a new class of viral fusion proteins (Class III). The structure of VSV‐G has been solved in two different conformations and fusion is known to be triggered by low pH. To investigate Class III fusion mechanisms, molecular dynamics simulations were performed on the VSV‐G prefusion structure in two different protonation states: at physiological pH (pH 7) and low pH present in the endosome (pH 5). Domain IV containing the fusion loops, which need to interact with the target membrane, exhibits the highest mobility. Energetic analyses revealed weakened interaction between Domain IV and the protein core at pH 5, which can be attributed to two pairs of structurally neighboring conserved and differentially protonated residues in the Domain IV–core interface. Energetic calculations also demonstrated that the interaction between the subunits in the core of the trimeric VSV‐G is strengthened at pH 5, mainly due to newly formed interactions between the C‐terminal loop of Domain II and the N‐terminus of the adjacent subunit. A pair of interacting residues in this interface that is affected by differential protonation was shown to be the main effectors of this phenomenon. The results of this study thus enhance the mechanistic understanding of the effects of protonation changes in VSV‐G. Proteins 2012. © 2012 Wiley Periodicals, Inc. 相似文献
5.
Theodoros K. Karamanos 《Biopolymers》2023,114(3):e23530
Coevolution between protein residues is normally interpreted as direct contact. However, the evolutionary record of a protein sequence contains rich information that may include long-range functional couplings, couplings that report on homo-oligomeric states or even conformational changes. Due to the complexity of the sequence space and the lack of structural information on various members of a protein family, it has been difficult to effectively mine the additional information encoded in a multiple sequence alignment (MSA). Here, taking advantage of the recent release of the AlphaFold (AF) database we attempt to identify coevolutionary couplings that cannot be explained simply by spatial proximity. We propose a simple computational method that performs direct coupling analysis on a MSA and searches for couplings that are not satisfied in any of the AF models of members of the identified protein family. Application of this method on 2012 protein families suggests that ~12% of the total identified coevolving residue pairs are spatially distant and more likely to be disordered than their contacting counterparts. We expect that this analysis will help improve the quality of coevolutionary distance restraints used for structure determination and will be useful in identifying potentially functional/allosteric cross-talk between distant residues. 相似文献
6.
Our notions of protein function have long been determined by the protein structure–function paradigm. However, the idea that protein function is dictated by a prerequisite complementarity of shapes at the binding interface is becoming increasingly challenged. Interactions involving intrinsically disordered proteins (IDPs) have indicated a significant degree of disorder present in the bound state, ranging from static disorder to complete disorder, termed ‘random fuzziness’. This review assesses the anatomy of an IDP and relates how its intrinsic properties permit promiscuity and allow for the various modes of interaction. Furthermore, a mechanistic overview of the types of disordered domains is detailed, while also relating to a recent example and the kinetic and thermodynamic principles governing its formation. 相似文献
7.
Increasing the affinity of binding proteins is invaluable for basic and applied biological research. Currently, directed protein evolution experiments are the main approach for generating such proteins through the construction and screening of large mutant libraries. Proliferating cell nuclear antigen (PCNA) is an essential hub protein that interacts with many different partners to tightly regulate DNA replication and repair in all eukaryotes. Here, we used computational design to generate human PCNA mutants with enhanced affinity for several different partners. We identified double mutations in PCNA, outside the main partner binding site, that were predicted to increase PCNA‐partner binding affinities compared to the wild‐type protein by forming additional hydrophobic interactions with conserved residues in the PCNA partners. Affinity increases were experimentally validated with four different PCNA partners, demonstrating that computational design can reveal unexpected regions where affinity enhancements in natural systems are possible. The designed PCNA mutants can be used as a valuable tool for further examination of the regulation of PCNA‐partner interactions during DNA replication and repair both in vitro and in vivo. More broadly, the ability to engineer affinity increases toward several PCNA partners suggests that interaction affinity is not an evolutionarily optimized trait of this system. Proteins 2013. © 2012 Wiley Periodicals, Inc. 相似文献
8.
Higurashi M Ishida T Kinoshita K 《Protein science : a publication of the Protein Society》2008,17(1):72-78
Proteins that can interact with multiple partners play central roles in the network of protein-protein interactions. They are called hub proteins, and recently it was suggested that an abundance of intrinsically disordered regions on their surfaces facilitates their binding to multiple partners. However, in those studies, the hub proteins were identified as proteins with multiple partners, regardless of whether the interactions were transient or permanent. As a result, a certain number of hub proteins are subunits of stable multi-subunit proteins, such as supramolecules. It is well known that stable complexes and transient complexes have different structural features, and thus the statistics based on the current definition of hub proteins will hide the true nature of hub proteins. Therefore, in this paper, we first describe a new approach to identify proteins with multiple partners dynamically, using the Protein Data Bank, and then we performed statistical analyses of the structural features of these proteins. We refer to the proteins as transient hub proteins or sociable proteins, to clarify the difference with hub proteins. As a result, we found that the main difference between sociable and nonsociable proteins is not the abundance of disordered regions, in contrast to the previous studies, but rather the structural flexibility of the entire protein. We also found greater predominance of charged and polar residues in sociable proteins than previously reported. 相似文献
9.
王泽峰 《生物化学与生物物理进展》2023,50(5):892-899
缓步动物（tardigrades,俗称水熊虫）等一些低等动物可在干燥、低温、低压等极端条件下长期生存。这种超常的生存能力依赖于细胞在大幅度脱水后,进入一种叫做隐生（cryptobiosis）的特殊状态,使细胞脱水、身体萎缩并停止新陈代谢,从而可以允许动物在极端条件下生存多年。当环境好转时,处于隐生状态的细胞或者身体又可以再次吸收水份进行复苏。缓步动物中有着多种独特的内在无序蛋白质（intrinsic disorder protein）,统称为热溶性蛋白质。这些热溶性蛋白质在细胞脱水过程中构象发生重要变化,可对液态水进行固定,从而起到了重要的细胞保护作用。对此类蛋白质的性质研究尚处于初期阶段,缺乏深入的机理性研究。本文简要总结了缓步动物中特有热溶性蛋白质的序列特征、理化性质,及其潜在的生物功能与机制。同时讨论了这些热溶性蛋白质在高等动物细胞对低温、低氧等极端环境适应中的可能应用。人类细胞在极端环境中的隐生和可逆复苏,将在医学领域和未来宇宙探索与星际移民中有极其重要的用途。 相似文献
10.
Konda Mani Saravanan A. Keith Dunker 《Journal of biomolecular structure & dynamics》2013,31(16):4338-4351
More than 60 prediction methods for intrinsically disordered proteins (IDPs) have been developed over the years, many of which are accessible on the World Wide Web. Nearly, all of these predictors give balanced accuracies in the ~65%–~80% range. Since predictors are not perfect, further studies are required to uncover the role of amino acid residues in native IDP as compared to predicted IDP regions. In the present work, we make use of sequences of 100% predicted IDP regions, false positive disorder predictions, and experimentally determined IDP regions to distinguish the characteristics of native versus predicted IDP regions. A higher occurrence of asparagine is observed in sequences of native IDP regions but not in sequences of false positive predictions of IDP regions. The occurrences of certain combinations of amino acids at the pentapeptide level provide a distinguishing feature in the IDPs with respect to globular proteins. The distinguishing features presented in this paper provide insights into the sequence fingerprints of amino acid residues in experimentally determined as compared to predicted IDP regions. These observations and additional work along these lines should enable the development of improvements in the accuracy of disorder prediction algorithm. 相似文献
11.
Muro-Pastor MI Barrera FN Reyes JC Florencio FJ Neira JL 《Protein science : a publication of the Protein Society》2003,12(7):1443-1454
Glutamine synthetase (GS) is the key enzyme responsible for the primary assimilation of ammonium in all living organisms, and it catalyses the synthesis of glutamine from glutamic acid, ATP, and ammonium. One of the recently discovered mechanisms of GS regulation involves protein-protein interactions with a small 65-residue-long protein named IF7. Here, we study the structure and stability of IF7 and its binding properties to GS, by using several biophysical techniques (fluorescence, circular dichroism, Fourier transform infrared and nuclear magnetic resonance spectroscopies, and gel filtration chromatography) which provide complementary structural information. The findings show that IF7 has a small amount of residual secondary structure, but lacks a well defined tertiary structure, and is not compact. Thus, all of the studies indicate that IF7 is a \"natively unfolded\" protein. The binding of IF7 to GS, its natural binding partner, occurs with an apparent dissociation constant of K(D) = 0.3 +/- 0.1 microM, as measured by fluorescence. We discuss the implications for the GS regulation mechanisms of IF7 being unfolded. 相似文献
12.
Iakoucheva LM Brown CJ Lawson JD Obradović Z Dunker AK 《Journal of molecular biology》2002,323(3):573-584
The number of intrinsically disordered proteins known to be involved in cell-signaling and regulation is growing rapidly. To test for a generalized involvement of intrinsic disorder in signaling and cancer, we applied a neural network predictor of natural disordered regions (PONDR VL-XT) to four protein datasets: human cancer-associated proteins (HCAP), signaling proteins (AfCS), eukaryotic proteins from SWISS-PROT (EU_SW) and non-homologous protein segments with well-defined (ordered) 3D structure (O_PDB_S25). PONDR VL-XT predicts >or=30 consecutive disordered residues for 79(+/-5)%, 66(+/-6)%, 47(+/-4)% and 13(+/-4)% of the proteins from HCAP, AfCS, EU_SW, and O_PDB_S25, respectively, indicating significantly more intrinsic disorder in cancer-associated and signaling proteins as compared to the two control sets. The disorder analysis was extended to 11 additional functionally diverse categories of human proteins from SWISS-PROT. The proteins involved in metabolism, biosynthesis, and degradation together with kinases, inhibitors, transport, G-protein coupled receptors, and membrane proteins are predicted to have at least twofold less disorder than regulatory, cancer-associated and cytoskeletal proteins. In contrast to 44.5% of the proteins from representative non-membrane categories, just 17.3% of the cancer-associated proteins had sequence alignments with structures in the Protein Data Bank covering at least 75% of their lengths. This relative lack of structural information correlated with the greater amount of predicted disorder in the HCAP dataset. A comparison of disorder predictions with the experimental structural data for a subset of the HCAP proteins indicated good agreement between prediction and observation. Our data suggest that intrinsically unstructured proteins play key roles in cell-signaling, regulation and cancer, where coupled folding and binding is a common mechanism. 相似文献
13.
Cory D. DuPai Bryan W. Davies Claus O. Wilke 《Protein science : a publication of the Protein Society》2021,30(3):613
The beta hairpin motif is a ubiquitous protein structural motif that can be found in molecules across the tree of life. This motif, which is also popular in synthetically designed proteins and peptides, is known for its stability and adaptability to broad functions. Here, we systematically probe all 49,000 unique beta hairpin substructures contained within the Protein Data Bank (PDB) to uncover key characteristics correlated with stable beta hairpin structure, including amino acid biases and enriched interstrand contacts. We find that position specific amino acid preferences, while seen throughout the beta hairpin structure, are most evident within the turn region, where they depend on subtle turn dynamics associated with turn length and secondary structure. We also establish a set of broad design principles, such as the inclusion of aspartic acid residues at a specific position and the careful consideration of desired secondary structure when selecting residues for the turn region, that can be applied to the generation of libraries encoding proteins or peptides containing beta hairpin structures. 相似文献
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15.
Kevin A. Cannon Rachel U. Park Scott E. Boyken Una Nattermann Sue Yi David Baker Neil P. King Todd O. Yeates 《Protein science : a publication of the Protein Society》2020,29(4):919-929
In recent years, new protein engineering methods have produced more than a dozen symmetric, self‐assembling protein cages whose structures have been validated to match their design models with near‐atomic accuracy. However, many protein cage designs that are tested in the lab do not form the desired assembly, and improving the success rate of design has been a point of recent emphasis. Here we present two protein structures solved by X‐ray crystallography of designed protein oligomers that form two‐component cages with tetrahedral symmetry. To improve on the past tendency toward poorly soluble protein, we used a computational protocol that favors the formation of hydrogen‐bonding networks over exclusively hydrophobic interactions to stabilize the designed protein–protein interfaces. Preliminary characterization showed highly soluble expression, and solution studies indicated successful cage formation by both designed proteins. For one of the designs, a crystal structure confirmed at high resolution that the intended tetrahedral cage was formed, though several flipped amino acid side chain rotamers resulted in an interface that deviates from the precise hydrogen‐bonding pattern that was intended. A structure of the other designed cage showed that, under the conditions where crystals were obtained, a noncage structure was formed wherein a porous 3D protein network in space group I213 is generated by an off‐target twofold homomeric interface. These results illustrate some of the ongoing challenges of developing computational methods for polar interface design, and add two potentially valuable new entries to the growing list of engineered protein materials for downstream applications. 相似文献
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Thomas A. Collier Anthony Nash Helen L. Birch 《Journal of biomolecular structure & dynamics》2019,37(2):537-549
Type I collagen is an essential extracellular protein that plays an important structural role in tissues that require high tensile strength. However, owing to the molecule’s size, to date no experimental structural data are available for the Homo sapiens species. Therefore, there is a real need to develop a reliable homology model and a method to study the packing of the collagen molecules within the fibril. Through the use of the homology model and implementation of a novel simulation technique, we have ascertained the orientations of the collagen molecules within a fibril, which is currently below the resolution limit of experimental techniques. The longitudinal orientation of collagen molecules within a fibril has a significant effect on the mechanical and biological properties of the fibril, owing to the different amino acid side chains available at the interface between the molecules. 相似文献
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19.
Floudas CA 《Biotechnology and bioengineering》2007,97(2):207-213
This review presents the advances in protein structure prediction from the computational methods perspective. The approaches are classified into four major categories: comparative modeling, fold recognition, first principles methods that employ database information, and first principles methods without database information. Important advances along with current limitations and challenges are presented. 相似文献
20.
ProADD, a database for protein aggregation diseases, is developed to organize the data under a single platform to facilitate easy
access for researchers. Diseases caused due to protein aggregation and the proteins involved in each of these diseases are
integrated. The database helps in classification of proteins involved in the protein aggregation diseases based on sequence and
structural analysis. Analysis of proteins can be done to mine patterns prevailing among the aggregating proteins.