"Misfolded" proteins also have positive energy

Prolonging life is something everyone hopes to achieve in themselves In order to live a long life, ancient emperors such as Qin Shihuang and Han Wudi spent huge human, material and financial resources to find a panacea Scientists have been exploring the regulatory mechanism of aging and longevity, trying to develop drugs that can prolong human life Starting from the important substance of life - protein, it may be easier to find the life code related to longevity   It is very important to keep the "body posture" of protein As we all know, protein is an important component of all the cells and tissues of human body All the important components of human body need the participation of protein As the main undertaker of life activities, protein not only participates in the catalysis of various biochemical reactions, but also plays an important role in the body structure, information transmission, immune defense, etc Generally, all kinds of physiological and biochemical processes inside and outside cells need not only specific functional proteins, but also these protein molecules to form corresponding high-level structures and shapes Therefore, the state of protein directly affects the physiological and biochemical reactions of the body   A large number of previous studies have shown that abnormal aggregation of proteins will bring negative effects on cells and organisms Protein molecules are composed of non branched peptide chains From newly synthesized peptide chains to proteins with specific three-dimensional structure and physiological functions, complex and fine peptide chain folding and processing are required   Due to the small energy difference among various folding modes, many factors, including the change of self concentration, the loss or extension of a part of peptide chain in the molecule, the change of amino acid residue caused by gene mutation, the change of pH value in the environment, the change of ion concentration, the change of sub environment around, etc., can change the folding mode of peptide chain One of the consequences of the change of peptide folding mode is the formation of special β - folding Not only that, such folding structure is also easy to cause "normal" proteins to change the folding mode and become the same structure as them, so these structural proteins have "infectivity", that is to say, they can copy their own structure, collectively referred to as "infectious proteins"   In many cases, this "misfolded" protein will lose its original physiological function, and its polymer will be harmful to cells, causing central nervous system diseases such as Alzheimer's disease, Huntington's dance disease, amyotrophic lateral sclerosis, etc   Protein aggregation can also perform important functions However, in recent years, many studies have shown that protein aggregation can bring positive effects on organisms, which can regulate cell division, early development of embryos, innate immune response of the body and other processes For example, proteins with the characteristics of prion like aggregation can be used to perform some normal and even very important physiological functions, including the formation of functional structure, storage, memory, as a template and information transmission, due to their stability and structural characteristics These functions have become an indispensable part of life activities   Recently, it was found that protein aggregation has positive biological function Drosophila is harmless to human body It has the most comprehensive type of gene mutation, the most abundant means of genetic hybridization, and the most complete transgenic lines It is one of the most ideal materials for biological experiments   The family proteins represent a large group of de ubiquitination proteases OTU protein of Drosophila is the first member of OTU family identified, and it has the characteristics of binding RNA But compared with other OTU family members, OTU protein of Drosophila has a unique enzyme activity center Interestingly, the OTU protein of Drosophila also contains a classical LC domain, but its biochemical and biophysical properties are unknown Chinese scholars have studied the enzymological characteristics and biological functions of OTU in Drosophila for a long time and systematically It is found that LC domain regulates the phase transition of OTU protein and plays an indispensable role in the "self aggregation" behavior of OTU protein It is important that OTU, as an active protease, can catalyze the ubiquitination of substrate Further studies have shown that RNA promotes "self aggregation" of OTU by binding to the LC domain of OTU protein and positively regulates its enzyme activity   Based on the model of Drosophila, jishanming group studied the enzymatic characteristics and biological functions of Drosophila OTU protein It was found that the low complexity domain could regulate the liquid-liquid phase transition process of Drosophila OTU protein and play an important role in the "self aggregation" process of OTU and the activity of de ubiquitinase Ribonucleic acid promotes "self aggregation" of OTU protein by binding to its low complexity domain, and regulates its enzyme activity positively When the expression of OTU protein is abnormal or the aggregation of protein is blocked, the gut immune signal of Drosophila will be disordered, the barrier function will be damaged and the life span will be shortened   At the same time, it was found that the "self aggregation" behavior and enzyme activity of OTU protein in vivo is a controllable process The molecular chaperone bam and OTU protein form a complex, which can promote the aggregation of OTU protein, enhance its ubiquitinase activity, and assist in the regulation of intestinal immune signal and life span At the same time, the expression of molecular chaperone BAM changes dynamically with the increase of age During the growth and aging process of Drosophila, the dynamic change of BAM affects and regulates the activity of OTU, so as to regulate the life span of Drosophila   This study shows that protein aggregation can effectively maintain the immune homeostasis in the intestine of Drosophila, improve the intestinal barrier function, and thus prolong the life of Drosophila   It can improve the balance of intestinal flora or prolong life For human beings, there are dozens or even hundreds of times more microorganisms than human cells, including bacteria, fungi, yeast and viruses These microorganisms are widely distributed in the skin, mouth, digestive tract, respiratory tract, reproductive tract and other parts of the human body, as well as the internal organs of the human body and blood nervous system It is estimated that there are at least 40000 kinds of microorganisms in the human intestine   Under normal circumstances, human beings and these intestinal microorganisms form mutually beneficial symbiotic complex through co evolution Intestinal tract provides the best living environment for microorganisms, including natural anaerobic conditions, rich nutrients, suitable temperature and pH value, etc., forming the place with the largest population density and genetic diversity unit area in the world   At the same time, these microorganisms and their metabolites also directly or indirectly affect the processing of nutrients, digestion and absorption, energy balance, immune function, gastrointestinal development and maturation and other important physiological activities The mutual benefit of both sides can maintain the stability and dynamic balance of human intestinal micro ecosystem   However, in today's deteriorating environment, in addition to antibiotics and all kinds of abused drugs, food preservatives, food preservatives, food pigments, etc., which are easy to be ignored, are destroying the dynamic balance of symbiosis between human beings and microorganisms At the same time, people's irregular diet, partial diet, excessive consumption of vegetables and fruits with pesticides, as well as stress and anxiety caused by work and life stress will destroy the balance of intestinal microorganisms   The disordered intestinal flora can easily reach other tissues and organs of human body through the intestinal tract, causing various diseases and seriously threatening human life Therefore, the maintenance of intestinal barrier function is of great significance to maintain the harmonious coexistence of intestinal microorganisms and human body, and to maintain human life and health   The discovery of the positive regulation function of protein aggregation can not only help us to better understand the protease activity and individual physiological process, but also enlighten us Maybe using the effect of protein aggregation can improve the intestinal flora of human body, so as to achieve the effect of strengthening body and prolonging life.