Biosynthesis of protein

Vadim Avenirovich KozlovDoctor of Biological Sciences,Candidate of Medical Sciences,corresponding member of RAE

Lecture 5ReplicationTranslationSplicing

Folding

Transcription

Translation

Ultimate proteolysis

Nucleic acids region

Proteins life stages

Cytoplasmic region

Post-translation modification

genes

procariots eucariots

genes

There are no exons and introns ExonsIntrons

do not carry genetic

information

carry genetic information

GEN - a section of the DNA molecule, in which information is recorded about one polypeptide chain

and, therefore, the mRNA molecule(there are rRNA and tRNA genes)

Here are recorded “translations machines"

At present, there is a situation where we do not have a clear understanding that there is a gene. Therefore, the definitions of textbooks do not correspond to reality and therefore several new definitions of this concept are pending.

Human Genome Nomenclature Organization, a gene is a "segment of DNA that affectsa phenotype or function. In the absence of the manifested function, a gene can becharacterized by sequence, transcription, or homology "Wang J. Genomic organization, transcript variants and comparative analysis of the human nucleoporin 155 (NUP155) gene / J. Wang [et al.] // Gene. – 2002.– Vol. 288. – P. 9–18.

Sequence Ontology Consortium, the gene is the "localized region of the genomesequence corresponding to the heredity unit that is associated with regulatory,transcriptional and other functional regions of the sequence"Pearson H. Genetics: what is a gene? // Nature. – 2006. – Vol. 441 (7092). – P. 398–401.

Ensembl (совместный проект European Molecular Biology Laboratory, EuropeanBioinformatics Institute и Wellcome Trust Sanger Institute) – «all transcripts obtainedas a result of alternative splicing belong to the same gene, even if they produce differentproteins»Wade N. 2003. Gene sweepstakes ends, but winner may well be wrong. New York Times.http://query.nytimes.com/gst/fullpage.html?sec=health&res=9A02E0D81230F930A35755C0A9659C8B63

A gene is a subroutine in the operating system of the genomeGerstein M. B., Bruce C., Rozowsky J. S., Zheng D., Du J., Korbel J. O., Emanuelsson O., Zhang Z. D., Weissman S., Snyder M. What is a gene, post-ENCODE?History and updated definition // Genome Research. – 2007. – № 17. – P. 669–681.

STAGES OF PROTEIN SYNTHESIS

TRANSCRIPTION

TRANSLATION

POSTRANSLATIONMODIFICATION

INICIATION

ELONGATION

TERMINATION

Необходимые условия

Нуклеиновые кислоты

Много ферментов

Много энергии (АТФ)

Рибосомы

Аминокислоты

Ионы Mg2+

PROPERTIES OF THE GENETIC CODE

Triplet

Degeneracy(redundancy)

Unambiguity

Non-Overlapping

Continuity Universalism

1954, theoretically proved that when a combination of 4 nucleotides with triples, 64 different combinations are obtained, which is enough to "record hereditary information"

(theoretical physicist)

Robert William Holly, USA

Har GobindKoran, USA

Marshall Warren Nirenberg, USA

1957 A.N. Belozersky and A.S. Spirin showed that the AT (U) / GC-composition of RNA of 19 species of bacteria as a whole is independent of the AT (U) / GC-DNA composition, that is, with significant differences in the nucleotide composition of DNA from different organisms, the nucleotide composition of total RNA is very similar .Based on these data, they came to the sensational conclusion that the total RNA of the cell can not act as a carrier of genetic information from DNA to proteins, because it does not correspond to it in its composition.

academicianA.N. Belozersky

academicianA.S. Spirin

RNA

iRNA (mRNA) tRNA rRNA

RNA, which is responsible for

transferring information about

the primary structure of

proteins from DNA to the sites of protein synthesis

RNA, the function of which is the

transportation of amino acids to the

site of protein synthesis and

participation in the growth of the polypeptide chain

The main function is the realization of the process of

translation -reading of

information from mRNA with amino

acids.

It is 3-5% of the total RNA in the cell.

It accounts for approximately 15% of

all cellular RNA.

It is 80% of the total RNA of the cell

A greatly overrated estimate, because there was not much known about the large number of small nuclear and cytosolic RNAs

when this was calculated.

Topoisomerase

Helicase (DNA-gyrasePrimaseRNA-primer

DNA-protein satellitesPolimarase IIIdimer

Polimarase IIIdimer

Lead chain Backward chain

RNA-primerOkazaki fragments

Ligase

Polimerase I

Structural elements of RNA polymerase

The clamp holds theDNA

Matrix DNA strand (front duplex)

Spike separates RNA and DNA hybrid

RNA

Mg2+

The damper participates in termination and transcription

β

β`

The F helix bends and stretches the DNA, ensuring the movement of the DNA matrix along the enzyme

Transcription: new RNA molecules form a "feather" around the DNA template

Bacterial Polymerase(structure of core-enzyme)

right view left viewsubunit

β`

Subunitβ

Central channel

Mg2+

yellow indicates the elements of thestructure (flap, spike and F-helix), shown in the previous figure

So it looks like transcription - the synthesis of RNA for the subsequent production of proteinBy Fdardel (Own work), via Wikimedia Commons

CONSTITUITIVESPLAYSING - from the English. to splice: splice

The intron is looped and excised as a sigma

the anatomy of the mRNA molecule

Cap 5`NTR AUG Translation region STOP 3`NTR poliA

Signals of initiation of translation by the scanning mechanism

Transcoding signals

Frame Shift

Ribosome Jump

The codon meaningchanging

Intracellular localization

signalRegulatory elements

Elements of mRNA instability

Internal initiation

signal

Signals of cytoplasmic and

nuclear polyadenylation

Alternative splicing allows individual genes to produce multiple protein isoforms - allowing the generationof complex proteomes.

In 1980, E. B. Ziff discovered that the Drosophila geneencoding one of the axon receptor proteins can form38016 different information RNAs as a result of directedrecombination of its sites. This gene contains 95alternative exons. Ziff E. B. Transcription and RNAprocessing by the DNA tumor viruses / E. B. Ziff //Nature. – 1980. – Vol. 287, № 5782. – P. 491–499.

Types of alternative splicing

Almost all human genes encode more than one protein - approximately 94% of human genes are subjected to an alternative splicing.

In most genes, alternative splicing is tissue-specific: in some tissues, one isoform is synthesized more often, in others, others are synthesized.

All human genes that do not undergo alternative splicing (6% of them) do not contain introns!

Thus, introns as well as exons encode instructions for protein synthesis.

One egg twin with different skin color

Marcia and Millieat birth

were absolutelysimilar,

but to the first class ...

The girls were born as a result of artificialcontrolled impregnationand came from one egg, separated at the stage of16 blastomeres.This is the result of a different reading of thesame genome

A similar case. The black and white monotonous twinsHaley and Lauren Derrant proudly hold their new sistersLeah and Mia - also twins with different colored skins!

3d model ribosomes

Nobel Prize 2009 in Chemistry

Venkatraman Ramakrishnan, USA, Distribution of protein andRNA in the 30S ribosomal subunit // Science. 1986. -28;231(4745):1562-4;

Thomas Steitz, USA, Visualizing polynucleotide polymerasemachines at work // EMBO J. 2006 August 9; 25(15): 3458–3468.From the structure and function of the ribosome to newantibiotics (Nobel Lecture) // Angew Chem Int Ed Engl. 2010 Jun14;49 (26):4381-98;

Ada Yonath, Israel, High-resolution structures of large ribosomalsubunits from mesophilic eubacteria and halophilic archaea atvarious functional States. // Curr Protein Pept Sci. 2002Feb;3(1):67-78. Review.

Lecture 6

Translation

TranslationThe structure of the protein-synthesizing system includesthe following structures: ribosomes are nucleoproteins containing approximately

60% ribosomal RNA and 40% of various proteins matrix RNA transport RNA protein factors and enzymes of initiation, elongation

and termination of translation amino acid set a set of aminoacyl-tRNA synthetases forming

aminoacyl-tRNA macroergies of ATP and GTP Ions of Mg, Ca, K, NH4

Activation of free amino acids precedes the beginning oftranslation and is carried out with the help of specific aminoacyl-tRNA synthetase enzymes in the presence of ATP.This process proceeds in two stages, both being catalyzed by oneenzyme.

Some aminoacyl-tRNA synthetases consist of one polypeptide chain,others - from two or four identical chains, each with a molecularweight of 35 to 115 kDa. Some dimeric and tetrameric enzymesconsist of subunits of two types.

Glutaminyl tRNA synthetase

At the first stage, the amino acid reacts with ATP, the pyrophosphate isreleased and an intermediate is formed which reacts with the corresponding3'-OH-tRNA in the II stage, resulting in formation of aminoacyl-tRNA (aa-tRNA) and releasing AMP.

Aminoacyl-tRNA has the necessary energy reserve andhas the following structure:

N

N

N

NO

NH2

O

OH O

CH2

тРНК Amino acid chine

C

HC

H2N R

O

Translation

Initiation-ribosome

recognitionthe start codon

and the beginning of the synthesis

Elongation-synthesis proper

squirrel

Termination-recognition of a stop codon (stop codon)

andproduct separation

Page 33

ELONGATION FACTORS

In eukaryotes

eEF-1α

eEF-1αβ

eEF-2

In prokaryotes

EF-Tu

EF-Ts

EF-G

Page 34

STAGES OF ELONGATION

I. Codon recognition and aminoacyl-tRNA binding

II. Formation of peptide bondIII. Translocation

Page 35

Codon recognition and aminoacyl-tRNA binding

Aminoacyl-tRNA is delivered to the free A-site of the ribosome with the participation of the elongation factor Tu.The elongation factor Tu forms a complex with GTP, which occurs with all aminoacyl-tRNA in the cytoplasm.Tu has GTPase activity and hydrolyses GTP.The complex undergoes dissociation only in the presence of the second elongation factor Ts, in which the released factor Tu can again rejoin the GTP molecule to participate in the delivery of aa-tRNA to the ribosome.Formylmethionyl-tRNA is located in the translating 70S ribosome in the peptidyl center, and aminoacyl-tRNA (the first amino acid after methionine) in the A-center.

Page 36

In the ribosome, an enzymatic transpeptidation reaction occurs between formylmethionyl-tRNA in the P-center and a new a-tRNA in the A-center.The residue of formylmethionine is transferred to the free NH2-group of aa-tRNA and the first peptide bond is closed in the future polypeptide chain.From the peptidyl center, tRNAfMet is released into the

cytosol.The enzyme that catalyzes the transpeptidation reaction is peptidyltransferase.During the transpeptidase reaction in the A-center, dipeptidyl-tRNA is formed, and the P-center remains free ("vacant").

Formation of peptide bond

Page 37

TranslocationIt is necessary to have a free amino-acyl center for attachment of the next aa-tRNA.The resulting fragment of dipeptidyl-tRNA is transferred from the aminoacyl to the peptidyl center.A translocation is achieved due to the movement of the ribosome relative to the mRNA with the participation of the translocase enzyme (it is performed by the elongation factor G) by using the energy of the decay of yet another GTP molecule.As a result of translocation, dipeptidyl-tRNA takes place in the peptidyl center of the ribosome, and the aminoacyl center is released for a new recognition cycle and can attach a new next a-tRNAcorresponding to the mRNA codon.In the process of translocation, the ribosome moves along the mRNA towards its 3 'end at a distance of one codon, i.е. exactly one triplet.

Page 38

Initiation complex. The interaction between the eIF4F complex, 43Sand mRNA is shown. EIF4F is formed be eIF4A, eIF4G and eIF4E.The complex 43S is formed by eIF3, the small ribosomal subunit andeIF2, witch in turn is formed by methionine-tRNA-initiator (Met-tRNAi)and GTP. The mRNA is recruited to the eIF4 complex across theinteraction of the 3` end and poly-A-binding protein (PABP) and the 5`cap and eIF4. UTR: untranslated region.

PROCAROTES AND ECUARIOTES USE TWO DIFFERENT WAYS TO THE INITIATIVE CODON

In higher organisms - eukaryotes - the ribosomal particle first joins the 5 'end of the mRNA, and then moves along the mRNA chain and scans it until it encounters the initiating codon. This method was called terminal initiation.

Scannig

Eukaryotes

Translation

Start Stop

PROCAROTES AND ECUARIOTES USE TWO DIFFERENT WAYS TO THE INITIATIVE CODON

Unicellular prokaryotic organisms use internal initiation.

In this case, the ribosomal particle binds directly to the local mRNA structure containing the initiating codon, independently of the 5 'end of the mRNA and its distance from the beginning of the coding sequence.

Blind multiple search of the beginning of reading Prokaryotes

Translation

Start Stop

Elongation - this is the actual translation of the coding sequence of the mRNA ribosome.It has two aspects:genetic (scanning of meaningful codons of mRNA) andbiochemical (synthesis of a polypeptide chain). When the scanning ribosome encounters a triplet of nucleotides in the elongation process, which does not encode any amino acid), the translation terminates: the polypeptide synthesis ceases and it is released from the ribosome.

Methionine is always a fierstamino acid in any protein, but

after the termination of synthesis it can be disconnected, the protein can be split into smaller secondary proteins that will no longer begin

with methionine

tRNAanticodone

loop

tRNAPhenilalanine

anticodoneloop

The vacant A-site takes the first elongator aminoacyl-tRNA in a complex with the elongation factor EF1 and GTP, after which GTP is hydrolyzed, EF1 with HDF leaves the ribosome, and the elongational aminoacyl tRNA bound in the A region remains side by side with the initiator methionyl tRNA bound in the P region.As a result, aminoacyl-tRNA is able to react with initiator methionyl-tRNA in the transpeptidation reaction catalyzed by a large ribosome sub-particle:Met-tRNAi + Aa-tRNAe → Met-Aa-tRNAe + tRNAi.This is how the first peptide bond is formed.

due to triplet-triplet binding (codon-anticodon interaction) between mRNA and tRNA in the ribosome, the translocation of tRNA each time leads to the stretching of the mRNA chain relative to the ribosome exactly by three nucleotides.

Since the ribosome is asymmetric and the translocation moves tRNA only unidirectionally from the A-site to the P-site, the pluripotent movement of the mRNA chain is also strictly polar, unidirectional. In the process of translocation (elongation), it can occur only in the direction from the 5 'to the 3' end of the chain.

The growth of the peptide in the ribosome goes from the N-terminus to the C-terminus

In the process of moving, the ribosome disintegrates all the double-helix segments that occur in its path and more complex elements of the secondary and tertiary structure of mRNA.

In prokaryotes, translation can be performed simultaneously with transcription

Transcription

RNA

Start

DNA

RNA-polimarase

The ribosome can contain no more than 10-30 amino acid residues of the growing polypeptide, counted from its C-terminus or peptidyl transferase center. As a rule, the complete polypeptide chains of ribosomal synthesized proteins consist of 100-300 or more amino acid residues. Therefore, some time after the start of translation, the N-terminal part of the growing polypeptide is outside the ribosome and then, as the polypeptide grows, an increasing portion of it is suspended from the ribosome into the medium. This creates conditions for the folding, compactification, and self-organization of the out-ribosomal part of the growing polypeptide into a spatial (secondary and tertiary) structure. Consequently, the folding of the polypeptide into a compact structure occurs as it grows, i.e. during translation, and therefore also polar, from the N-terminus to the C-terminus. Such a gradual polar folding of the growing polypeptide chain on the ribosome is referred to as cotranslational formation of the protein structure (cotranslational folding).

TERMINATION: RELEASE OF POLYPEPTIDE AND DISSOCIATION OF RIBOSOMAScanning the mRNA chain by triplets and, accordingly,

lengthening the polypeptide chain, the ribosome translating reaches the end of the coding sequence and occurs with one of three triplets that do not encode amino acids and are referred to as stop codons or termination codons-UAG, UAA or UGA (formerly called insignificant , or meaningless, triplets).

As a result of the final translocation, the polypeptidyl-tRNA is linked to the last significant triplet in the P-site of the ribosome, and the termination codon is established in the A-site.

In the cell, there is no aminoacyl-tRNA capable of complementary binding to the termination codon, and therefore the A-site is not filled with the usual acceptor substrate, which is aminoacyl-tRNA.

Instead, special proteins, called termination factors, or release factors (RF) come into play.

TERMINATIONRF1 (or similar RF2) interacts directly with the termination codon in the A site, and the other, RF3, with the assistance of the first and with the participation of GTP -with a large ribosome subparticle and possibly directly with the peptidyl transferase center. The result of the binding of these factors to the ribosome is the targeting of the hydrolase activity in the ribosome: the peptidyl transferase center of the ribosome catalyzes the interaction of polypeptidyl-tRNA as a donor substrate with the water molecule as an acceptor substrate.

TERMINATIONThe connection between the synthesized polypeptide (its C-

terminus) and tRNA is hydrolyzed and the polypeptide is no longer retained in the ribosome and is released into the solution as a finished protein.

The final act of termination is the release of deacylated tRNAfrom the P-site and the dissociation of the ribosome into subparticles. Dissociation occurs spontaneously due to the weakening of the bond between the two ribosomal subparticles in the absence of ligands (peptidyl-tRNA and aminoacyl-tRNA), it can be significantly accelerated by a special protein called the ribosome release factor.

Proteins post-translation modification

Post-translational modificationsPost-translational modifications (lat. post - after and lat.translatio - transmission; lat. modus - measure, type and facio- do] - enzymatic changes in the chemical structure of proteinmolecules after the completion of their synthesis on theribosomes, ch. arr. in the endoplasmic reticulum and Golgiapparatus.

For many proteins, post-translational modification is the finalstage of biosynthesis, which is part of the gene expressionprocess.

Biochemical reactions of post-translational modification ofproteins are not matrix type reactions, they are called step-like reactions.

posttranslational modifications can be:

widespread rare, up to unique

posttranslational modifications are divided into:

modificationsmain chine

modificationsside chains (residue)

of amino acids

Modifications to the main circuit1. Incorporating cleavage of peptide bondremoval of the N-terminal methionine residuerestricted proteolysis2. Accession of small chemical groupsN-acylationN-ArginylationC-amidation3. The addition of hydrophobic groups for

localization in the membraneN-myristoylation the addition of glycosylphosphatidylinositol (GPI)

Modifications of the side chains of amino acids1. Accession or splitting off of small

chemical groupsglycosylationN-glycosylationO-glycosylationhydroxylationacetylationmethylationγ-carboxylationO-sulfonationphosphorylationiodinationoxidationglycationdisulfide bond formationdeiminationcarbamoylationdeamidation

2. The attachment of hydrophobic groups for localization in the membrane

prenylation - attachment of remains of isoprenoids (farnesyl and geranylgeranyl)

S-palmitoylation

Phosphorylation

Phosphorylation (phosphorylation) [Greek. phos- light and phoros - carrier] - the process of inclusion in various molecules of the orthophosphoric acid, carried out by enzymes of the class of phosphotransferases.

For the discovery of reversible phospholysis of proteins, E. Fisher and E. Krebs received the Nobel Prize in 1992.

GlycosylationGlycosylation [Greek. glykys - sweet] - modification of

protein, lipid or DNA, expressed in covalent attachment to the molecule of the carbohydrate residue. In the posttranslational protein, carbohydrate components are most often represented by N-acetylgalactosamine, L-fucose and sialic acid. For proteins, N-G is distinguished. (carried out on the NH2-group of asparagine located through one amino acid residue from tryptophan) and OG. (occurs predominantly in the OH group of serine and threonine).

Methylation

Methylation) [franch. methyle — groupe — CH3, from the Greek methy — vine, hony & hyle —tree; wood alcohol] — Enzymatic addition to the biological macromolecule (protein, DNA, RNA, polysaccharides) of the methyl group (— CH3)

Acetylation

Acetylation) [from lat. acetum — vinegar] —posttranslational modification of proteins by covalent attachment of acetyl groups to them, which is reflected in their functional activity.

For example, local acetylation of N-terminal histone sites at the post-translational level is associated with chromatin activation; Acetylation of the p53 protein at the COOH end stimulates its ability to bind to DNA.

RibosylationRibosylation) [from angl. ribose — ribose, from the

permutation of letters in English. arabinose -arabinose] - the covalent attachment of ribose to the protein molecule as a result of posttranslational modification, which leads to a change in its properties. Ribosylation serves, for example, as one of the mechanisms of the pathogenic action of toxins on the cell.

The process of ribosylation was discovered by Yu. Nishizukaya et al. in 1968

CitrullingCitrullination (lat. citrullus is watermelon and -in (e)

is a suffix for "like"] - the process of post-translational modification of proteins, leading to the conversion of arginine to citrulline, which is catalyzed by the enzyme peptidyl-arginine deiminase.

For example, some filamentous proteins (filaggrin, vimentin) appearing in patients with rheumatoid arthritis, which is used for highly sensitive diagnosis of the disease, are often prone to citrulling.

MyristylationMyristylation [from lat. myristica — nutmeg]

is a post-translational modification of some proteins, consisting in the chaining of a fatty myristic (tetradecanoic acid) chain consisting of 14 carbon atoms to the N-terminal amino acid (usually glycine). Myristylation is characteristic, for example, for viral proteins, for a number of eukaryotic protein kinases; it promotes their normal functioning in the cell.

For the first time, protein myristylation was discovered by A. Aitken et al. in 1982

SumoylationSumoylation [from angl. s(mall) u(biquitin-related)

mo(difier) — small ubiquitin-related modifier] is a post-translational modification of the protein, consisting in the covalent binding of the epsilonamine group of lysine located at the C-terminus of the polypeptide to the SUMO protein, which is a component of the ubiquitin system. The protein summation affects various cellular processes, such as the regulation of gene expression, mitosis, apoptosis, and others.

Sumoylation was first described by T. Sternsdorff et al. in 1997

LipidationLipidation [from Greek. lipos & eidos] —

post-translational modification of the protein, including N-terminal myristylation, addition of cholesterol residues to the C-terminus of the polypeptide, addition of farnesyl and heroin-geronyl groups to the C-terminal cysteine residues, and palmitylation of these residues along the molecule. Lipidation of proteins increases their affinity for membranes, which affects the intracellular localization and function of the lipoproteins formed.

PrenylationPrenylation (English). pr (opyl) ene - propylene] is

a post-translational modification of the protein, which involves the addition of farnesyl and heroin-geronylgroups to the C-terminal cysteine residues.

PalmitylationPalmitylation [lat. palmes (palmitis) - palm branch]

- post-translational modification of some proteins (eg, rhodopsin, protein, consisting in the attachment to the sulfhydryl cysteine group of the amino acid chain of aliphatic palmitic acid (see Palmitic acid) consisting of 16 carbon atoms.

Signal sequence, signal peptide

Signal sequence, signal peptide) [lat. signum] is a short amino acid sequence (15-50 amino acids) located at the N- or C-terminus or occasionally inside secretory and transmembrane proteins, which determines the direction of their transport in the cell after translation and promotes the penetration of molecules through the membranes into the extracellular space

For the discovery of the Signal sequence G. Blobel received the Nobel Prize for 1999.

Protein splicing was discovered in 1990 by a group of T. Stevens.During protein splicing, the removal of excess genetic information from macromolecules occurs not at the level of pre-mRNA, as during constitutive splicing, but at the level of the synthesized polypeptide by actocatalytic excision of its short amino acid sequence from its internal part.

Intein and N-extein form a complex thioether

intein is linked by a peptide bond to C-extein

intein is now completely cut out of N- and C-exteins

Some proteins contain within their chain three consecutive sections: N-extein, intein and C-extein. Intein has autocatalytic activity, flexes, converts the ends of exteins together, connects them, loops and disappears from the protein as a ring.

Intain disconnects

and collapses

Protein folding

The peptide tends to assume a conformation with amaximum of hydrogen bonds. However, the possibilityof their formation is limited by the fact that thepeptide bond has a partially double character, sorotation around it is difficult. The peptide chain doesnot acquire an arbitrary but strictly definedconformation, fixed by hydrogen bonds.

The amino acid sequence is not the only factordetermining the shape of the protein molecule. In thecell there are special molecules that activelyparticipate in protein folding.

Shaperones

1. Molecules that ensure the correct folding of proteins (folding-chaperones - folding chaperones).2. Molecules created to hold a partially folded protein molecule in a specific position. This is necessary for the system to be able to finish folding (holding chaperones).3. Chaperones unfolding proteins with irregular shape (disaggregating chaperones).4. Chaperones accompanying proteins transported through the cell membrane (secretory chaperons).

Chaperones, in addition to their basic function of laying proteins, also carry out other functions associated with changing the conformation of proteins, namely:

transport of many proteins from one compartment to another,participation in signaling pathwaysregulation of the functions of various molecules

Bacteria Archea

Eycariotes

Thermosome

Prefoldin

mRHA

Trigger factor

Other chaperones

Prefoldin

HSP90system

HSP90system

ChaperoninTRIC/CCT

CohaperoninGroES

Proteins, evolutionarily related to the protein GroEL, were called chaperonins. The role of chaperonins is to provide optimal conditions for effective folding.

Each of the 14 subunits of the oligomeric molecule of chaperonin can participate in the binding of the collapsing protein (in the "molten globule" state). The number of binding sites depends on the stage of folding: the closer the structure to the native, the less the areas "recognized" by chaperonin.

Protein folding is accompanied by a decrease in the internal energyof the molecule and its dissipation in the form of heat.

Disease Etiology Characteristic pathology

Prion diseases (kuru, Kreuzfeld-Jakob disease, fatal familial insomnia, Gerstmann-Straussler-Sheinkerdisease)

Sporadic, genetic or infectious Spongy degeneration, amyloids and other aggregates

Amyotrophic lateral sclerosis Sporadic Taurus Bonn, axonal spheroids

Parkinson's disease Sporadic α-synuclein, parkin Taurus Levy

Front-temporal dementia Mutations of tau protein Taurus Peak

Alzheimer's disease Sporadic, presenilin Neurite plates

Huntington's disease Huntingtin Intranuclear inclusions, cytoplasmic aggregates

Other polyglutamine diseases Ataxin-1,3 and others. Intranuclear inclusions

Energy-dependent destruction of the protein

1930 Rudolf Schoenheimer - there is a delicate balancebetween protein synthesis and degradation.1960 Avram Hershko - protein degradation is an activeprocess that requires energy in the form of ATP.Gideon Goldstein, as a result of the search for factors ofdifferentiation of lymphocytes, isolated a polypeptide witha mass of 8 kD and named it the ubiquitin "ubiquitousimmunopoietic peptide" (UBIP).1980 Hershko, Aaron Cehanover, Alexander Varshavskydiscovered the enzymes:group E1 - catalyzing ATP-dependent activation ubiquitingroup E2 - forming poly-ubiquitin chainsgroup E3 - catalyzing the binding of ubiquitin to targetproteins.

Kiss of death -ubiquitivation

(energy-dependent proteolysis of proteins)

1980 Irwin Rose, Avraham Hershko and Aaron Cechanover // PNAS found an ATP-dependent addition of ubiquitin to proteins before they were placed in proteasomes, for further proteolysis.

Proteasome

Ubiquitination (Lat. ubique is ubiquitous and -in (e) is a suffix meaning "like"] - the process of attaching to the protein a "chain" of ubiquitin molecules (see Ubiquitin). At Y. the connection of the C-terminus of ubiquitin with the side residues of lysine occurs in the substrate. The polyubiquitin chain is hung at a specific time and is a signal that the protein is degradable. A certain protein promotes its degradation with the help of proteolytic enzymes contained in proteasomes (see Proteasomes). The process was first described by A. Hershko in 1979 (the Nobel Prize for 2004 jointly with I. Rose and A. Cichanover).