ubiquitin

Small proteins present in all eukaryotes

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Ubiquitin（ ubiquitin ）It is a kind of Eukaryote (Most Eukaryotic cell ）Small proteins in. Ubiquitin consists of 76 amino acid composition , molecular weight is about 8.451kDa. Its main function is to mark what needs to be decomposed protein , making it 26S Proteasome Degradation. 26S proteasome upregulation Subunit Some receptors on K48 and K11 can recognize polyubiquitinated proteins linked by K48 and K11. The 20S core subunit is located in ATPase Energy supply Lower hydrolysis substrate. Ubiquitin can also label transmembrane proteins and participate in the vesicular transport 。 Atypical ubiquitin chain in Cell signal transduction ， Endocytosis , and DNA damage repair , Regulation NF- κ B It plays an important role in the pathway. It has a high degree of Conservatism 96% of human and yeast ubiquitins Similarity 。

Chinese name: ubiquitin
Foreign name: ubiquitin
Alias: Ubiquitin

chemical reaction: The occurrence of a series of catalytic reactions
Location: majority Eukaryotic cell Small proteins in
Reaction: Three enzyme cascade reaction
Role: Protein degradation, DNA damage repair

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Ubiquitin is a kind of ubiquitous in eukaryotic cells Small molecule Protein, 76 in size Amino acid residue 。 Ubiquitin can pass through Enzymatic reaction And then mediate the degradation of target proteins.

chemical reaction

The whole process of the occurrence of a series of catalytic reactions is called ubiquitination signaling pathway. In the first step, ubiquitin activating enzyme (also called E1) hydrolyzes ATP And a ubiquitin molecule Adenylate Change. Next, ubiquitin is transferred to E1 active center Of Cysteine Residue With adenosylation of the second ubiquitin molecule. The adenosylated ubiquitin molecule is then transferred to the second enzyme, ubiquitin Conjugating enzyme (E2). Finally, highly conservative Ubiquitin ligase A member of the (E3) family (depending on the substrate protein) recognizes specific target proteins that need to be ubiquitinated, and catalyzes the transfer of ubiquitin molecules from E2 to target proteins. It is generally believed that the target protein is Proteasome Before recognition, the polyubiquitin chain formed by at least four ubiquitin monomers at K48 or K11 must be labeled. However, the latest research shows that the ubiquitin chain formed by two ubiquitin monomers can be more effectively degraded by proteasome. In general, E3 makes this system substrate specific, and E2 or E2-E3 determines the type of ubiquitin chain on the substrate. The amount of E1, E2 and E3 proteins depends on the organism and cell type. There are a lot of different E3 proteins in the human body, which indicates that Ubiquitin proteasome system It can act on a large number of target proteins.

How polyubiquitinated proteins are recognized by proteasomes has not been fully understood. The N terminal of ubiquitin receptor protein has a ubiquitin like protein Domain , and one or more ubiquitin binding domains. Ubiquitin like domains can be identified by 19S regulatory particles, while ubiquitin binding domains can bind ubiquitin by forming triple helix bundles. These receptor proteins may be able to bind polyubiquitinated proteins and carry them to Proteasome However, the specificity and regulatory mechanism of this binding are still unclear. Finally, the labeled protein is protease It is decomposed into smaller polypeptides amino acid And ubiquitins that can be reused.

In 2004, aaron ciechanover 、 Avram Hershko 、 Owen Ross The discovery of ubiquitin mediated Protein degradation Process Nobel Prize in Chemistry 。

A Brief History of Ubiquitin

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Discovery process

molecular surface of ubiquitin

In retrospect of the discovery of ubiquitin, we cannot but mention two pioneering studies. The discovery of ubiquitin dates back half a century. In 1953, Simpson used the radio isotope conduct Metabolism experiment , published“ Biological cell In Proteolysis Medium needs Metabolic energy That is, those requiring ATP Water decomposition ”Thesis of. However, this epoch-making research has been ignored for a long time. at that time thermodynamics Add water decomposition reaction It is the capacity response, and the energy required Synthetic reaction Different, this process does not require energy. Another pioneering research is Goldberg et al.'s paper (1977), which reported the phenomenon observed by Simpson reproduced in vitro. This paper wakes up Simpson's discovery sleeping at the bottom of the library. Goldberg et al red blood cell Of Extract The addition of ATP significantly promotes protein decomposition, that is, energy consumption is accompanied by protein decomposition. In this discovery, select Reticulocyte It is unique. Goldberg et al. noticed that when reticulocytes finally differentiate into red blood cells, they no longer need nuclei, Organelle ， lysosome The protein in the cell decomposes rapidly in the cell, that is protein synthesis Among the active reticulocytes, its decomposition activity is also very high. It can be said that this choice determines everything. In fact, if ATP was not added to the reticulocyte extract, Simpson's experimental observation The discovery of ubiquitin may be many years away. ATP dependence The discovery of proteolysis in vivo suggests a possible biochemical mechanism.

The above research and other information Proteolysis The miraculous phenomenon of is beginning to attract people's attention. In the early 1960s, we found organelles full of hydrolytic enzymes-- lysosome Therefore, it is considered as the main organ for protein decomposition. But the non selective destruction mode of lysosome is difficult to explain that Organelle The contradiction between protein individuals with different life span and expression levels. However, at that time, this was only a minority opinion and gradually disappeared. But in the 1970s, with the lysosomal function inhibitor The cells treated with these reagents still have constant Proteolysis It is difficult to inhibit, which indicates that there is a protein decomposition system different from lysosome. Based on these observations, it was called "non lysosomal protein decomposition system" at that time. Before long, this "non lysosomal protein decomposition system" was combined with the aforementioned "ATP dependent protein decomposition system".

In order to maintain the acidic pH in lysosomes and organelles Metabolic energy However, these energies come from the role of membrane ATP pump (ATPase), which is similar to that observed by Goldberg et al cytoplasm Of Energy consumption The mechanism of is completely different. Actually, like Escherichia coli Such organelle free prokaryote The protein decomposition of Proteolytic enzyme System and lysosomal system exist independently of each other. Then, the ATP dependent proteolytic enzyme Lon enzyme (common serine Protease and ATP pump Enzyme structure Of Multifunctional enzyme )。 Goldberg et al. believed that Eukaryotic cell ATP dependent proteolytic enzymes also exist in. At that time, the Goldberg team who discovered and established the reticulocyte system also had absolute confidence in discovering the ATP dependent mechanism, but there was an unexpected scenario in this big play, which took away all the glory they expected to win in "discovering the ATP dependent protein decomposition mechanism in eukaryotic cells", It is the superstars Hershko and Varshavsky who break the dream of Goldberg's team

From the Identification of APF-1 to the Discovery of Ubiquitin

Hershko advocated“ Inducible enzyme ”And the famous Tomkin Research Lab reported Steroid hormone Induced Tyrosine Transferases Of half life Significantly shortened, which Catabolism Energy is required. In 1971, he returned to his motherland Israel , continue Proteolysis In 1977, he was inspired by Goldberg et al., who used reticulocytes, and other related papers such as "ATP dependent proteolysis system", and worked with Ciechanover, who was a graduate student at that time, to explore its mechanism. They are separated by chemical methods, purification Stage related factors in reticulocyte extract. Soon, in 1978, the "Phase 1" of DEAE cellulose method and the high concentration of adsorption were obtained Salting out Phase 2 of. Fortunately, these operations are only commonly used to red blood cell Internal massive hemoglobin Biochemical analysis method for removal. It is almost difficult to see the promoting effect of ATP in Phase 1 and Phase 2 alone, but when they are mixed, the promoting effect of ATP can be observed. This result shows that the ATP dependent protein decomposition pathway is complex and was published in BBRC (1978) in the form of bulletin. They regard this essay as their most proud achievement, and even in their speeches, they often mention it.

Shortly thereafter, the ATP dependent proteolysis factor (APF-1) was successfully purified in Phase 1. APF-1 Yes thermal stability Good small molecule protein. At that time, it was assumed that APF-1 existed in Phase 2 and had not yet been identified Proteolytic enzyme I125 labeled APF-1 was used to detect its interacting molecules. But the results showed a surprising phenomenon. 125I-APF-1 appeared in the form of polymer ladder, and it was clear that this modification reaction was carried out in ATP with water decomposition reaction Is necessary. It was natural for this phenomenon to be regarded as polyubiquitination, but it was not difficult to imagine their surprise at that time. Different from the original expectation, in 1980, APF-1 was considered as the substrate protein and the energy consumed Covalent Combined products.

Now it is necessary to introduce the history of ubiquitin research, first in 1975, Goldstein Think of it as Thymic hormone However, it was soon clear that it was just a mixture of substances in the sample, that is, ubiquitin was a "wrongly discovered molecule". But it was in this research that the name "Ubiquitin" was created and spread in the history books. Goldstein et al Histiocyte It is ubiquitous in universality (ubiquity), called ubiquitin. In 1977, Goldknopf and Busch cell cycle In the study of chromosome Histone Different from 2A Peptide chain The bound molecule is ubiquitin. This article, "Ubiquitin covalently binds to protein", brings light to clarify the mechanism of Ubiquitin modification reaction. Then, in 1980, Hershko and his co researchers proved that APF-1 and ubiquitin are the same substance. The function of ubiquitin was verified again.

Hershko's Ubiquitin Hypothesis

Soon Hershko and Ciechanover proposed the hypothesis that ubiquitin plays a basic role in protein decomposition: ubiquitin passes E1 (activating enzyme), E2 (binding enzyme), E3（ Ligase ）Multi level reactions, covalently binding with the target protein, most of the ubiquitin molecules are branched together to form polyubiquitin chains, and polyubiquitin chains become markers of proteolytic enzyme attacks, and the target protein captured is rapidly decomposed. This "ubiquitin hypothesis" was later widely praised. The gist of this hypothesis is that Metabolic energy It is necessary for ubiquitin activation. Conceptually, ATP is consumed in the signal formation of protein decomposition. This hypothesis is completely different from the concept of ATP dependent proteolytic enzyme predicted by Goldberg et al., and this explanation of energy dependent protein decomposition mechanism is no less than a thunder in sunny days. It is necessary to note that this series of studies was conducted by biochemistry Methods, and Molecular Biology Technology No connection.

In the first five years when Hershko and Ciechanover proposed the ubiquitin hypothesis competitor This is extremely rare in peaceful times. Of course, this is also related to the fact that people at that time could not believe this "unimaginable phenomenon at that time" reliability People always cast suspicious eyes. This is also Originality Has reached the realm of transcendence, be too highbrow to be popular A typical example of. But this kind of originality is too high and often brings some misfortune. Because it is beyond common sense, Nature, Science and other world-class magazines do not believe their findings and refuse to publish them for a long time.

Study on the Genetics of Varshavsky

In the proof of the in vitro effect of the ubiquitin system, Varshavsky and his co researchers, who have many students (Finley, Jentsch, Hochstrasser, etc.), have made the greatest contribution, and are still active as leaders in the world. Varshavsky in 1977 Soviet Union Moscow chromosome The institute emigrated to the United States boston Of MIT （ MIT ）。 At that time, he was mainly engaged in chromosome research. Because of this relationship, he noticed Goldknopf and Busch's report on ubiquitin modification, and studied the chromosome related functions of ubiquitinated histone H2A. Taking this opportunity, around 1980, Varshavsky began to use the Reverse genetics Ubiquitin system is studied by using the. Then, the yeast genes corresponding to E1, E2, E3 and other enzyme groups identified by Hershko et al. in biochemistry were isolated one by one. These studies will clarify the function of ubiquitin chain as the actual signal decomposition in cells, and remove the hypothesis of "ubiquitin hypothesis" from the text. At the same time, they have made many prospective research results related to ubiquitin system through a series of genetic studies. At that time, a series of papers published in Nature, Science and Cell swept the world of protein decomposition in five years. Considering the impact of their research on later generations, their work is worthy of great praise.

Proteolysis Enzyme body Discovery of

As a wonderful example, the "ubiquitin hypothesis" still has a major defect from the perspective of energy dependent protein decomposition mechanism, which is that ubiquitin modification is just a device for ATP consumption. In 1983, the author and Goldberg proved that the ubiquitin modified Proteolysis It still needs ATP to decompose by adding water, so it advocates the "two-stage theory of ATP dependence in the process of protein decomposition". That is to say, although it has been proved that ubiquitin acts as an energy dependent signal attachment mechanism Proteolytic enzyme The concept of "attack marker" is correct, but actually the protein decomposition after ubiquitin modification still needs energy. The key point of this hypothesis lies in the molecular mechanism of ATP consumption as the second, and prokaryote Same, Eukaryote The same ATP dependent proteolytic enzyme also exists. This means that Goldberg's prediction before the debut of Ubiquitin was half correct. This inference led to the discovery of ATP dependent proteolytic enzymes called proteosomes. Proteasome first appeared in science It's 1988 in the magazine, but I understand it molecular structure More than 10 years later. The reason for taking such a long time is that this enzyme body is the largest and most complex molecular aggregate in the history of life science with a molecular weight of 2.5 million and a total sub base of 100.

Proteasome is Proteolytic enzyme The discovery of novel enzyme bodies, which are totally different in concept, can be called a TV series. As one of the parties involved in the discovery of this enzyme body and its subsequent research progress, I regret that I will not be able to tell the story of the discovery of proteolytic enzymes here. However, interested readers can Go to see my Personal homepage

Ubiquitin biological research Fuse

This article only tells the story of the discovery of ubiquitin, and it is difficult to summarize the subsequent progress of ubiquitin research in a word or two. The biological leap development of ubiquitin dependent protein decomposition system has led to the discovery of more and more diseases and patients related to it. This article only wants to describe an example of the research on its biological discovery precursors. In 1980 cell cycle A Japanese research team（ The University of Tokyo Emeritus professor Masato Yamada et al.) can induce Chromosomal abnormality Solidification temperature Receptivity And reported that the modified cells were found when cultured at unrestricted temperature Histone The ubiquitin of H2A disappears. At that time, Varshavsky, who studied the ubiquitination of histones, noticed this paper and obtained ts85 cells, which confirmed the existence of ts85 cells ubiquitin-activating enzyme E1 mutation, and the use of this cell proves that ubiquitin is involved in short-lived protein decomposition. This 1984 report was the first landmark paper on the physiological function of ubiquitin system in cells. At the same time, the study of ts85 cells has become an important means to study the importance of ubiquitin in the control of cell cycle.

In 1983, Hunt discovered that cell division CyclinB, a periodically changing protein, was published in 1991 by Hershko's team and Kirschner, cell cycle From then on, a new page was opened. Then Hershko separated the cyclinB ubiquitinated E3 ligase by biochemical method and named it cyclosome. This somewhat exaggerated name comes from the huge difference between the ubiquitized CyclinB and its 20S. But cyclosome was also cast a skeptical eye at first. "Is the so-called E3 enzyme the combination product of membrane or other unidentified molecules?". In 1996, there was an event that completely dispelled these doubts. Several different research teams around the world have explored the molecular structure of cyclosome, also known as APC (anaphase promoting complex). The results proved that APC is a giant molecular complex composed of more than 10 subunits. The enzyme is readily available as APC/C. next, Kyoto University Professor Yoshida Kazuhiro and Kim Nasmyth, through isolation of abnormal yeast induced in chromosomes being isolated genome , clarifying the composition of APC/C Subunit And its target molecules in most cases. This is to prove that cell cycle Controlling the crucial event of the importance of ubiquitin dependent proteolysis system. This result reveals the mystery of abnormal chromosome coagulation of ts85 cells at impermissible temperatures, and also makes it possible to Cell cycle M phase That is, the research on the mechanism of chromosome allocation has reached the molecular level. In the future study of cell cycle, the importance of ubiquitin system has become increasingly important. Especially new products such as SCF and Mdm2 Ubiquitin ligase The discovery of Ubiquitin and the study on them confirmed the central role of ubiquitin dependent protein decomposition in the regulation of check point in the smooth progress of cell cycle. These results established that the cell cycle was controlled by protein phosphorylation and ubiquitin Proteolysis The concept of control is called the greatest achievement of cancer research in recent years.

Later research on ubiquitin

It has been 20 years since Finley, Ciechanover and Varshavsky used ts85 cells in 1984 and published the article "Ubiquitin is related to intracellular protein decomposition" in Cell magazine. In 2004, Cell magazine published the recollection article of the client to commemorate this discovery. According to Pickart's memory related to this discovery, there were less than 100 articles related to ubiquitin in 1984 and more than 1000 in 2003. This also reflects the rapid development of ubiquitin research from the side. And in life sciences Every issue of Nature, Science and Cell, the top journals in the field, carries the topic of "Ubiquitin", and the research on Ubiquitin is still in rapid development without decline. Ubiquitin - Proteolytic enzyme Body as the determinant of numerous Living body The response can be rapid, sequential, Transitory , reasonable means of one-way operation cell cycle , apoptosis, Metabolic regulation ， immune response ， signal transmission ， Transcription control , quality management, stress response, DNA repair It has become an unshakable fact that many fields in life science have played a central role.

The research on ubiquitin has also achieved unexpected results. For example, in the study of ubiquitination of histones initially mentioned, it is also clear that ubiquitin also has Proteolysis External functions, such as Pinocytosis ， Vesicle transport Selection of, Viruses The material circulation system in cells such as budding, or DNA repair, Translation control Ubiquitin plays a role in signal transmission Signal molecule Role of. To take another example, there are many ubiquitin like molecules (i.e. ubiquitin like proteins) in cells, which independently form a huge "protein protein" After translation Of Decoration system ”。 They are critical to the Genetic information The control of amplification gene can play a role in gene Phantom Features not available on. What is more surprising is that the gene population associated with ubiquitin accounts for 2-3% of the total number of genes. Ubiquitin is really a common protein.

Hershko, Ciechanover, Varshavsky, who made contributions to the discovery of ubiquitin, were awarded Albert Lasker Award in 2000. The FASEB Summer Conference "Ubiquitin and Protein Degradation" sponsored by ershko, Goldberg, Varshavsky, etc. has made great contributions to the research progress of ubiquitin. The first session was held in 1989, the next year, and the eighth session was held in 2004. In the first session, the participants were mainly the above three great men and their disciples. It's just a small gathering of ubiquitin researchers. Now, this situation has changed. More than half of the participants are young researchers whom the author does not know. In addition, since 2003, CSH symposium In the future, the two meetings will be held alternately every year. And about Proteolytic enzyme The 6th Proteasome Workshop will be held in Clermont Ferrand (France) in 2005. In addition to these regular international meetings, Keystone Symposium and EMBO Workshop also frequently hold irregular meetings on the topic of ubiquitin. From these circumstances, Ubiquitin is in a period of vigorous development. But unfortunately, what the world will be like after the climax is still unknown. Can it really bring good news to the understanding of life, or is it still lingering in the abyss of mystery. As for the author, although he does not expect a long life span, he wants to bid farewell to the world when his research on ubiquitin sees the end of the dawn.

Ubiquitin effect

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Nobel Prize in Chemistry

In 2000, Hershko, Ciechanover, Varshavsky won Albert Lasker Basic Medicine Award. This award is said that half of its winners will win Nobel Prize Since then, Ubiquitin has been regarded as a candidate for the Nobel Prize. In the second year, 2001, the 34th Nobel Society, entitled "Regulation of cellular function by the ubiquitin proteasome system" Stockholm Karolinska Research Institute, in addition to Hershko, Ciechanover, Varshavsky, Goldberg and others cell cycle , immunology, neurology and other experts in this field. Then, as we all know, in 2004, Hershko, Ciechanover, Rose and other three people won the Nobel Prize in Chemistry.

Both the parties concerned and the researchers in related fields welcomed and surprised the Nobel Prize. Because "Rose instead of Varshavsky" and "Chemistry award instead of medical physiology award" unexpectedly.

Related impacts

Rose uses ATP Enzyme reaction The authority of science, together with Hershko and Ciechanover, conducted research at the early stage and made great contributions to the exploration of the mechanism of ubiquitin modification reaction. Since then, he has also made extraordinary achievements in talent cultivation. These three scholars have made great contributions in advocating the ubiquitin hypothesis by biochemical means at the beginning.

In my personal opinion, it is really regrettable that Varshavsky failed to win the Nobel Prize. Without Varshavsky's outstanding work, the current research on ubiquitin would be difficult to expand to the current level. Moreover, Varshavsky has published dozens of papers on the ubiquitin system in Nature, Cell, Science and other journals. In contrast, the number of 3 winners was almost 0. Perhaps this represents modern genetic engineering, molecular biology With the rapid development of modern technology, such progress itself should bring about significant progress in human gene analysis personal use Based on previous chemistry and enzymology The basic so-called Low tech The discovery of this new concept is of great significance. Therefore, awarding the Nobel Prize is a recognition of the original discovery. Nobel Committee It is to flaunt oneself to commend this "initial discovery". The modern highly developed life science has produced a large number of papers in mass production, and this award of the Nobel Prize in Chemistry can also be said to be a special warning for this truly original discovery.

Another thing is that after winning this prize nature Anecdotes published. Hershko planned to go swimming with his granddaughter the day after the Nobel Prize in Medicine and Physiology was announced, but he got the news of being awarded the Nobel Prize in Chemistry from his cousin (the Nobel Committee was informed by telegraph Laureate Before that, a short message was broadcast, and the cousin who heard the news informed me). In other words, it is extremely unexpected to win the chemistry prize. Yes, in recent years, the research of ubiquitin has been expanding in medicine, pathological physiology and other fields. Many people think that the prize of medical physiology should be awarded, but in fact, it is a chemical prize. This chemistry prize, it is necessary to focus on protein as ligand Is unique Regulatory mechanism Discovery of and Biological significance This focus problem should be correctly understood. Hershko's wisdom, Ciechanover's excellent technology and Mobility Rose's profound knowledge of enzymology, as a result of the joint efforts of three scientists with different personalities and talents, established the hypothesis that ubiquitin is a signal of protein decomposition. From the contributions of these three people to the establishment of basic concepts, I think I can probably understand the significance of the Nobel Prize in Chemistry.

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