Intrinsically Disordered Proteins

from Wikipedia, the free encyclopedia
The partially structured protein SUMO-1 (after PDB 1A5R ) with a relatively ordered structure in the central region and disordered structures in the C - and N -terminal regions.

An intrinsically disordered protein (short name: IDP , English: intrinsically disordered protein ) is a protein that lacks a fixed or ordered three-dimensional structure . IDPs comprise completely unstructured and partially structured proteins that contain, among other things, random coils and (pre-) molten globules . This also includes proteins with multi-part domains , the domains of which are linked with short peptide sequences (flexible linkers) . In some cases, IDPs can be converted into a solid structure by binding to other macromolecules .

They are not to be confused with the intrinsically unstructured proteins , which is a subgroup of the intrinsically disordered proteins. However, the terms are sometimes used synonymously in the literature.

history

The Anfinsen dogma states that the native structure of proteins under physiological conditions is determined by the amino acid sequence . In the 1960s, could show you that in denaturation of ribonuclease lost 99% of its enzymatic activity and had regained its enzymatic activity at reintroduction into their physiological condition. From this it could be concluded that the amino acid sequence alone was sufficient to fold the protein into a functional conformation with the lowest free energy. In 1972 Christian B. Anfinsen , Stanford Moore and William Howard Stein received the Nobel Prize in Chemistry for this discovery .

In the early 2000s, it was recognized that not all proteins functioned when folded. Therefore, some proteins would have to be unfolded or disordered in order to function. It is estimated that around 10% of proteins are disordered and 40% of eukaryotic proteins have at least one long (> 50 amino acids) disordered β-loop . Under physiological conditions in vitro, the amino acid sequences showed similar physical and chemical characteristics to those of random coils . Random coils are also little or no structured, do not have a tightly packed core, but instead have an extended conformation with high intramolecular flexibility.

Many crystallographic structures lacked β-loops and this was evident from a series of amino acids with missing atomic coordinates in the model. It was thought that the “gaps” in the model were artifacts from random glitches in the crystal. In some cases, these gaps may indicate intrinsically disordered β-loops in an otherwise folded protein. Such gaps are the basis for server as DISOPRED3, the intrinsically disordered regions (IDR, Eng. Intrinsically disordered region ) and can predict protein binding sites within these regions.

In 2011, Tanguy Chouard published a comprehensive overview and some functions of IDPs in the journal Nature .

properties

Regulation by post-translational modification leads to increased binding affinity between the IDPs and their receptors. It has been suggested that the flexibility of disordered proteins facilitates binding to modifying enzymes and their respective receptors. Proteins with intrinsic disorder are mainly involved in signal transduction , transcription and the remodeling of chromatin .

Flexible linkers

Disordered regions often appear as flexible linkers or loops that can bind protein domains to themselves. The amino acid sequences of flexible linkers vary widely in length, but they are rich in polar amino acids . Flexible linkers are able to twist and rotate the domains they are connected to, thus using the protein domain dynamics to attract binding partners. They also bind to proteins to give them more opportunities to change conformation through widespread allostery.

Linear motifs

Linear motifs are short sections of proteins that mediate functional interactions with other proteins or biomolecules, such as DNA, RNA, sugar, etc. They usually play an important role in cell regulation, for example the control of cell structure, subcellular localization of various proteins and the regulation of protein turnover. Most of the time, post-translational modification such as B. by phosphorylation, the affinity for certain interactions is modified. With the help of nuclear magnetic resonance , so-called PreSMos (pre-structured motifs) were recognized in 80% of the IDPs , which are involved as brief structural secondary elements in target recognition. In some cases, through binding to a target partner, the short-term structural secondary elements solidify and stabilize, for example they become helices. Presumably the PreSMos form the active centers of the IDPs.

Coupled folding and binding

Many disordered proteins go into a more ordered state upon binding, e.g. B. Molecular recognition features (MoRFs). The binding and coupled folding is only local and requires only a few interacting amino acid residues or an entire protein domain. Certain disordered regions serve as molecular switches that take on certain biological roles and, when bound, change to an ordered state, for example through binding to small molecules, binding to DNA / RNA, ion interactions, etc.

The ability of disordered proteins to bind in order to perform a function shows that the stability of the protein is not a condition for being able to perform a function. Many short functional sites, such as short linear motifs, are overrepresented in the disordered protein. Disordered proteins and short linear motifs are particularly numerous in RNA viruses , such as henipaviruses , hepatitis C virus , HIV-1 and human papillomaviruses , in order to enable the binding and manipulation of a large number of proteins in the host cell and thus their genome can transfer.

Disorder in the bound state (fuzzy complex)

Despite binding to other proteins, intrinsically disordered proteins can change their conformation at any time. This structural disorder can be static or dynamic when bound. Fuzzy complexes are protein complexes which consist of IDPs and which can change their conformation in the bound state at any time for the exercise of their biological function. The binding specificity of DNA-binding proteins can be influenced by alternative splicing in which the length of fuzzy regions is varied.

structure

Intrinsically disordered proteins adapt to the respective conditions of the cell by changing their conformation. The totality of all possible conformational states is referred to as a structural or conformational ensemble . Therefore, the structure of IDPs is heavily dependent on their function. However, only a small proportion of IDPs are completely disordered (in their native state). IDPs have specific areas, the intrinsically disordered regions (IDRs), which mainly determine the degree of disorder. For this reason, IDPs can be divided into completely disordered (intrinsically unstructured proteins) and proteins with IDRs.

Whether there is a disorder and what type of disorder is present is determined by the amino acid sequence. In general, IDPs are low in bulky amino acids (which can cause steric hindrance ) and are mostly rich in polar and electrically charged amino acids which cause low fat solubility (low hydrophobicity). This enables a good interaction with water. High total charges in the protein promote the disorder caused by electrostatic repulsion from amino acid residues of the same charge. Thus, IDPs are not able to fold into globular proteins, since no hydrophobic core can be formed by the electrostatic repulsions. In some cases, certain hydrophobic clusters in IDRs can make statements about which regions are subject to coupled folding and binding (through weak and non-specific binding to the target protein , also known as the fly casting effect).

Many IDPs do not have any regular secondary structures and are therefore referred to as flexible (which can be recognized by the various combinations of Ramachandran angles ). Flexibility does not refer to a state of equilibrium, as is the case with structured proteins. Many IDPs also have so-called low-complexity regions (LCRs), in which, for example, sequences of some amino acid residues or amino acid motifs are over-presented. LCRs are possible indicators of disorder, but not all IDPs have low-complexity regions .

Experimental evidence

Intrinsic disordered proteins, once purified, can be detected by various experimental methods. The most important method of obtaining information about disordered regions in protein is by means of NMR spectroscopy . In crystal structure analysis , the demonstrated lack of electron density can also be evidence of disordered regions.

Folded proteins have a high density (with a partial specific volume of 0.72–0.74 mL / g) and a small scattering mass radius that is roughly the same for every protein. Accordingly, methods are used that are sensitive to molecular size, density or water resistance, such as gel permeation chromatography , analytical ultracentrifuge , small-angle X-ray scattering (SAXS) and measurements of the diffusion coefficient . Unfolded proteins are characterized by their lack of secondary structural elements, which could be detected with far UV light (absorption maximum at 170–250 nm), circular dichroism (with a pronounced minimum at ~ 200 nm) or IR spectroscopy . Since the peptide bonds in the main chain of unfolded proteins are exposed to the solvent, they can easily be cleaved by proteases and then undergo a hydrogen-deuterium exchange . They have a low distribution (<1 ppm) of the 1 H-NMR shifts of the amide protons (folded proteins typically show a distribution of 5 ppm for their amide protons).

Recently, methods such as Fast parallel proteolysis (FASTpp) were introduced, which enable the determination of folded or disordered parts of the protein without prior purification. Even minor deviations in the stability of missense mutations, protein-protein interactions and protein folding through (self) polymerization of, for example, coiled coils can be detected by FASTpp, as was recently demonstrated in the tropomyosin-troponin protein interaction. Completely disordered protein regions can be detected with low protease concentrations with short exposure times due to their proteolytic susceptibility .

Complex methods for investigating the IDP structure and dynamics are, for example, SAXS (information about the structure of conformational ensembles ), NMR (subtleties at the atomic level), fluorescence (visualization of molecular interactions and conformational changes), crystal structure analysis (highlighting flexible regions in rigid protein crystals ), Cryoelectron microscopy (determination of solid structures of the protein), dynamic light scattering (to show the size distribution of IDPs or the aggregation kinetics) and circular dichroism (to determine secondary structures).

Methods for studying individual molecules of IDPs are, for example, spFRET (for determining the conformational flexibility and the kinetics of conformational changes), optical tweezers (for high-resolution structures of the conformational ensembles , oligomers or aggregates of IDPs), nanopores (for determining the distribution of spherical shapes in IDPs ), magnetic tweezers (for the investigation of long-term conformational changes with low force effects), and the atomic force microscope with high measuring speeds (to visualize the temporal-spatial flexibility of IDPs).

Intrinsic disorder

REMARK465 - lack of electron density in an X-ray crystal structure, which is due to an intrinsic disorder in the protein ( PDB  1a22 , human growth hormone bound to the receptor). Compilation of screenshots from the PDB and visualization using Visual Molecular Dynamics (VMD). The blue and red arrows indicate missing amino acid residues on the receptor and growth hormone.

Information on intrinsic disorder can be predicted from experimental data or with the help of specialized software. Algorithms for predicting intrinsic disorder (ID) or tendencies towards intrinsic disorder can be predicted with high accuracy (approx. 80%). The prediction is based on certain compositions of the primary structure , similarities of indefinite sections in data sets from crystal structure analyzes, flexible regions in NMR studies and on physicochemical properties of the amino acids.

Databases

Databases were set up for this purpose in order to be able to assign information on intrinsic disorder to certain protein sequences. The DisProt database contains a collection of protein sequences in which an intrinsic disorder has been determined experimentally. MobiDB is a database that combines information about the experimentally determined, intrinsic disorder (for example from DisProt ) with data from crystal structure analysis (about missing amino acid residues) and from NMR structures (from flexible regions).

Differentiation between IDPs and structured proteins

The separation of ordered and disordered proteins is necessary for predicting intrinsic disorder. To this end, it has been found that certain compositions of amino acids lead to the formation of an intrinsic disorder and a solid structure to develop in others. The hydrophilic, electrically charged amino acids alanine, arginine, glycine, glutamine, serine, proline, glutamic acid and lysine are amino acids that promote the intrinsic disorder in proteins. In contrast, the hydrophobic, uncharged amino acids tryptophan, cysteine, phenylalanine, tyrosine, isoleucine, valine, leucine and asparagine promote solid structures (order). The remaining amino acids histidine, methionine, threonine and aspartic acid can each be found in ordered and disordered regions. This information forms the basis of most sequence-based predictions. Regions with little or no secondary structure elements (also known as NORS, NO Regular Secondary structure ) as well as low-complexity regions can be easily discovered.

Forecasting methods

The determination of disordered regions using biochemical methods is very costly and time-consuming. Since IDPs are flexible in their structure, only certain aspects of their structure can be characterized. Thus, a large number of different methods and experiments would be necessary for a complete description of the structure, so that the costs for determining the IDP reach astronomical heights. To circumvent this problem, computer-based methods were developed that can predict protein structures and functions. IDP prediction programs often use structural information from protein interaction sites (short linear motifs). Other methods of IDP prediction include neural networks or matrix computation based on various structural and / or biophysical properties.

Some examples of software for predicting IDPs are IUPRED and Disopred. It should be noted that each method defines the term “clutter” differently. Meta-software for the prediction of IDPs combine different primary software, which could make the prediction more exact.

Different methods of IDP prediction make measuring the relative accuracy of the prediction difficult. For example, neural networks use a combination of different sets of data. The IDP prediction is a category of the joint experiment CASP , which tests different methods for their accuracy and how exactly they can find regions in proteins with a missing 3D structure. Missing 3D structures are marked as REMARK465 in PDB files ; in crystal structure analyzes this is indicated by the lack of electron density.

Clinical significance

Intrinsically disordered proteins play an important role in some diseases. An aggregation fehlgefaltener proteins can synucleinopathies lead. An example of an intrinsically disordered protein is α-synuclein . Due to its structural flexibility and its susceptibility to intracellular modification, it can lead to aggregation and misfolding. Genetic dispositions , oxidative and nitrosative stress as well as mitochondrial impairments can impair the structural flexibility of the unfolded α-synuclein and also lead to synucleinopathies. Many tumor suppressors have a large number of intrinsically disordered regions, such as p53 or BRCA1 . It is these regions that enable interaction with other proteins.

Computer simulations

Due to the high structural diversity of IDPs, parameters can be obtained with the aid of NMR / SAXS experiments, which represent the average values ​​for a large number of highly diverse and disordered states (a conformational ensemble for disordered states). In order to be able to understand these parameters, which give information about the structure of the protein, precise representations of the protein must be created with the help of computer simulations. So-called all-atom molecular dynamic simulations can be used for this, but have the disadvantage that the accuracy is impaired by the effects of force fields . Nevertheless, it was possible to develop force fields that can be used for the investigation of IDPs by optimizing the force field parameters with the aid of NMR data from IDPs (e.g. CHARMM 22 *, CHARMM 32, Amberff03 * and others).

Molecular dynamics simulations that are restricted by experimental parameters (also called restrained MD ) can also be used to characterize IDPs. In principle, MD simulations (with an exact force field) can be used to simulate entire conformational ensembles , as long as the simulation is carried out long enough. Because IDPs often have a high structural diversity, these simulations have to run for a long time with high computing power . Other computer simulations that run in a short time are the accelerated MD simulations , replica exchange simulations , metadynamics , multicanonical MD simulations or methods that use simplified representations of the protein.

Furthermore, one can use various methods and protocols for the analysis of IDPs, which are based on studies for the quantitative examination of the GC content in genes and their associated chromosome bands. This information can be used to make statements about the functions of certain IDP sections.

Individual evidence

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