Protamine

2AWR561919118ENSG00000175646ENSMUSG00000022501P04553P02319NM_002761NM_013637NP_002752NP_0386652AWR562019119ENSG00000122304ENSMUSG00000038015P04554P07978NM_001286356NM_001286357NM_001286358NM_001286359NM_002762NM_008933NP_001273285NP_001273286NP_001273287NP_001273288NP_002753NP_032959Protamines are small, arginine-rich, nuclear proteins that replace histones late in the haploid phase of spermatogenesis and are believed essential for sperm head condensation and DNA stabilization. They may allow for denser packaging of DNA in the spermatozoon than histones, but they must be decompressed before the genetic data can be used for protein synthesis. However, in humans and maybe other primates, 10-15% of the sperm's genome is packaged by histones thought to bind genes that are essential for early embryonic development. Protamines are small, arginine-rich, nuclear proteins that replace histones late in the haploid phase of spermatogenesis and are believed essential for sperm head condensation and DNA stabilization. They may allow for denser packaging of DNA in the spermatozoon than histones, but they must be decompressed before the genetic data can be used for protein synthesis. However, in humans and maybe other primates, 10-15% of the sperm's genome is packaged by histones thought to bind genes that are essential for early embryonic development. Protamine and protamine-like (PL) proteins are among the sperm specific nuclear basic proteins (SNBPs). The PL proteins are intermediate in structure between protamine and Histone H1, the C-terminal of which being the precursor of vertebrate protamine. During the formation of sperm, protamine binds to the phosphate backbone of DNA using the arginine-rich domain as an anchor. DNA is then folded into a toroid, an O-shaped structure, although the mechanism is not known. A sperm cell can contain up to 50,000 toroid-shaped structures in its nucleus with each toroid containing about 50 kilobases. Before the toroid is formed, histones are removed from the DNA by transition nuclear proteins, so that protamine can condense it. The effects of this change are 1) an increase in sperm hydrodynamics for better flow through liquids by reducing the head size 2) decrease in the occurrence of DNA damage 3) removal of the epigenetic markers that occur with histone modifications. The structure of the sperm head is also related to protamine levels. The ratio of protamine 2 to protamine 1 and transition nuclear proteins has been found to change the sperm head shape in various species of mice, by altering the expression of protamine 2 via mutations in its promoter region. A decrease in the ratio has been found to increase the competitive ability of sperm in Mus species. However, further testing is required to determine how this ratio influences the shape of the head and whether monogamy influences this selection. In humans, studies show that men who have unbalanced Prm1/Prm2 are subfertile or infertile. Protamine 2 is encoded as a longer protein that needs its N-terminal cleaved before becoming functional. Human and chimp protamine has undergone rapid evolution. When mixed with insulin, protamines slow down the onset and increase the duration of insulin action (see NPH insulin). Protamine is used in cardiac surgery, vascular surgery, and interventional radiology procedures to neutralize the anti-clotting effects of heparin. Adverse effects include increased pulmonary artery pressure and decrease peripheral blood pressure, myocardial oxygen consumption, cardiac output, and heart rate. Protamine sulfate is an antidote for heparin overdose, but severe allergy may occur. A chain shortened version of protamine also acts as a potent heparin antagonist, but with markedly reduced antigenicity. It was initially produced as a mixture made by thermolysin digestion of protamine, but the actual effective peptide portion VSRRRRRRGGRRRR has since been isolated. An analogue of this peptide has also been produced. In gene therapy, protamine sulfate's ability to condense plasmid DNA along with its approval by the U.S. Food and Drug Administration (FDA) have made it an appealing candidate to increase transduction rates by both viral and nonviral (e.g. utilizing cationic liposomes) mediated delivery mechanisms. Protamine may be used as a drug to prevent obesity. Protamine has been shown to deter increases in body weight and low-density lipoprotein in high-fat diet rats. This effect occurs through the inhibition of lipase activity, an enzyme responsible for triacylglycerol digestion and absorption, resulting in a decrease in the absorption of dietary fat. No liver damage was found when the rats were treated with protamine. However, emulsification of long-chain fatty acids for digestion and absorption in the small intestine is less constant in humans than rats, which will vary the effectiveness of protamine as a drug. Furthermore, human peptidases may degrade protamine at different rates, thus further tests are required to determine protamine’s ability to prevent obesity in humans.