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NSP4 also called Neutrophil Serine Protease 4 (NSP4) or Serine Protease 57 (PRSS57),is member of the peptidase S1 family of proteins. It is one of the neutrophil serine protease in the cytoplasmic granules of neutrophils. This enzyme is expressed in bone marrow and takes part of the immune response against pathogens. NSP4 is located in the telomeric region of the chromosome 19. The protein cleaves preferentially after Arg residues but also after citrulline and methylarginie residues.

Contents 1 Function 2 Disease 3 Relevance 4 Structural highlights

Function

Recruitement of neutrophils to the site of inflammation is the earliest defense reaction against pathogens. NSP4 is stored in the azurophilic granules [1] which is a compartment of neutrophils. In response to neutrophil activation, NSP4 is released into the pericellular environment where microbes are after their phagocytosis. The serine protease 54 not only kill pathogens but also regulate the activity of immune mediators such as chemokines and lymphocytes. [2] NSP4 alterates chemokines by proteolitically cleaving N-terminus of the chemokine.[3] Furthermore, the caspase-like activity of PRSS57 can activate lymphocytes and the adaptive immune response. However, although NSP4 can inactivate some inflammatory processes, the neutrophil serine protease generally promotes than inhibits the inflammatory response.

Disease

Granulocytes neutrophils are the most abundant leukocytes in the blood and are implicated in the immune system. They are the first defend barriers in the innate immunity. When a pathogen agent enters into the body, they recognize it thanks to its antigens and phagocyte the pathogen. They are quick and their recognition is non-specific, and not dependent on previous exposure to microorganisms.[[4]] It has also been shown that neutrophils have not only a phagocyte role but can influence all the innate and adaptive immune response by exchanging information with the other immune cells through soluble mediators or direct cell contact.[[5]] In this manner, deficiency in NSP4 might lead to neutrophil deficiency and have terrible consequences. Unfortunately, NP4 is not the more important serin protease of neutrophils, so there isn’t currently in vivo studies of the release of the protein, and any disease as yet been associated with a NSP4 dysfunction. Nevertheless, many studies have been released on the three most important neutrophil serin protease: neutrophil elastase (NE), cathepsin G (CG), and proteinase 3 (PR3). As they have quite the same function in the neutrophil, we can hypothesize that the diseases found related to those proteins are related to the diseases we might found with NSP4. For example, instead of phagocyte bacteria, neutrophils can begin an alternative cell death program leading the exchange of their nuclear chromatin by extracellular chromatin fibers covered with antimicrobial protease that can kill bacteria. [[6]] However, if neutrophils are over activated it could lead to autoimmune diseases against neutrophils serine proteases or hypersensitivity reactions. A disorder of neutrophil serine proteases as also been demonstrated in many genetic disorders like Higashi syndrome or Papillon-Lefevre syndrome.[[7]]

Relevance

Structural highlights

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The protein has a 283 amino-acids long sequence with two mainly domains . It forms a kind of elongate sphere of approximately 70Å large and 150Å long (dimensions: 70,37Å X 70,37Å X 105,02Å). The protein is composed of signal peptide (1-31) which leads to the location in azurophil granules [8] and allows its excretion. In addition there is a protease domain (32-283) which is a trypsin-like domain with a trypsin-like active site, according to the specificity for P1-Arg residues, but this domain can be an elastase-like active site according to the primary sequence (because of the presence of a swallow S1 pocket) specific to small aliphatic residues.^[1]

The active is form by 4 amino acids: Gly(189), Phe(190, Ser(216), D(226) The residue F190 obstructs the active site which could normally not links a P1-Arg. However, a study ^[2] considered the possibility that the two residues S216 and F190 of the active site can form a flexible gate which allows P1-Arg to enter. Then, the link between the active site and P1-Arg can be stabilized by a salt bridge interaction between S1-D226 and P1-Arg. The hypothesis of the flexible gate was confirmed by the same study. The mutations of S216 only, F190 only or both together show a forced full open gate is more efficient than a forced partially open gate.

The conclusion is that the protease domain is a trypsin-like domain.