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Protamine P1
Symbol Protamine_P1
Pfam PF00260
InterPro IPR000221
protamine 1
Symbol PRM1
Entrez 5619
HUGO 9447
OMIM 182880
RefSeq NM_002761
UniProt P04553
Other data
Locus Chr. 16 p13.13
protamine 2
Symbol PRM2
Entrez 5620
HUGO 9448
OMIM 182890
RefSeq NM_002762
UniProt P04554
Other data
Locus Chr. 16 p13.13

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 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.[1]


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.[2] 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 1) increase in sperm hydrodynamics for better flow through liquids by reducing the head size 2) decrease the occurrence of DNA damage 3) remove the epigenetic markers that occur with histone modifications.[3]

The structure of sperm head is also related to the 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 Mus, the genus 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 has an impact on this selection. In humans, studies show that men who have imbalanced Prm1/Prm2 are subfertile or infertile.[4]

Medical uses[edit]

When mixed with insulin, protamines slow down the onset and increase the duration of insulin action (see NPH insulin).[5]

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.[6]

Protamine sulfate is an antidote for heparin overdose.[7] A chain shortened version of protamine also acts as a potent heparin antagonist, but with markedly reduced antigenicity.[8]

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[9] and nonviral (e.g. utilizing cationic liposomes)[10] 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.[11]


Mice, humans, rat [12] and certain fish have two or more different protamines, whereas the sperm of bull and boar,[13] have one form of protamine due to a mutation in the PRM2 gene.


The 2 human protamines are denoted PRM1 and PRM2.


Examples of protamines from fish are:

Protamine structure[edit]

The primary structure of protamine P1, the protamine used for packaging DNA in sperm cells, in placental mammals is usually 49 or 50 amino acids long. This sequence is divided into three separate domains: an arginine-rich domain for DNA binding flanked by shorter peptide sequences containing mostly cysteine residues. The arginine-rich domain consists of 3-11 arginine residues and is conserved between fish protamine and mammalian protamine 1 sequences at about 60-80% sequence identity.[14] After translation, the protamine P1 structure is immediately phosphorylated at all three of the above mentioned domains. Another round of phosphorylation occurs when the sperm enters the egg, but the function of these phosphorylations is uncertain. When protamine P1 binds to DNA, cysteine from the amino terminal of one protamine P1 forms disulfide bonds with the cysteine from the carboxy-terminal of another protamine P1. The disulfide bonds function to prevent the dissociation of protamine P1 from DNA until the bonds are reduced when the sperm enters the egg.[15]

The secondary and tertiary structure of protamine is not known with certainty, but several proposals have been published.[16][17][18]


  1. ^ Balhorn R (2007). "The protamine family of sperm nuclear proteins". Genome Biol 8 (9): 227. doi:10.1186/gb-2007-8-9-227. PMC 2375014. PMID 17903313. 
  2. ^ Brewer L (October 1999). "Protamine-Induced Condensation and Decondensation of the Same DNA Molecule". Science 286: 120–123. doi:10.1126/science.286.5437.120. 
  3. ^ Woop M (January 2015). "Optimizing Tethered Particle Motion to Measure DNA Compaction by Protamine". Biophysical Journal 108: 393a. 
  4. ^ Luke L (March 2014). "Sexual selection on protamine and transition nuclear protein expression in mouse species". The Royal Society. doi:10.1098/rspb.2013.3359. 
  5. ^ Owens DR (June 2011). "Insulin preparations with prolonged effect". Diabetes Technol. Ther. 13 Suppl 1: S5–14. doi:10.1089/dia.2011.0068. PMID 21668337. 
  6. ^ Carr JA, Silverman N (1999). "The heparin-protamine interaction. A review.". J Cardiovasc Surg (Torino) 40 (5): 659–66. PMID 10596998. 
  7. ^ Weiler JM, Freiman P, Sharath MD, Metzger WJ, Smith JM, Richerson HB, et al. (1985). "Serious adverse reactions to protamine sulfate: are alternatives needed?". J Allergy Clin Immunol 75 (2): 297–303. doi:10.1016/0091-6749(85)90061-2. PMID 2857186. 
  8. ^ Byun Y, Chang LC, Lee LM, Han IS, Singh VK, Yang VC (2000). "Low molecular weight protamine: a potent but nontoxic antagonist to heparin/low molecular weight protamine". Asaio J. 46 (4): 435–9. doi:10.1097/00002480-200007000-00013. PMID 10926141. 
  9. ^ Kenneth Cornetta, W.French Anderson (1989). "Protamine sulfate as an effective alternative to polybrene in retroviral-mediated gene-transfer: implications for human gene therapy". Journal of Virological Methods 23 (2): 187–194. doi:10.1016/0166-0934(89)90132-8. PMID 2786000. 
  10. ^ Sorgi, FL; Bhattacharya, S; Huang, L (Sep 1997). "Protamine sulfate enhances lipid-mediated gene transfer." (PDF). Gene therapy 4 (9): 961–8. doi:10.1038/ PMID 9349433. 
  11. ^ Duarte-Vazquez MA (May 2009). "Effect of protamine in obesity induced by high-fat diets in rats". International Journal of Obesity 33: 687-692. doi:10.1038/ijo.2009.78. 
  12. ^ (PDF)  Missing or empty |title= (help)
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  14. ^ Balhorn R (September 2007). "The protamine family of sperm nuclear proteins". Genome Biology. doi:10.1186/gb-2007-8-9-227. 
  15. ^ Balhorn R (September 2007). "The protamine family of sperm nuclear proteins". Genome Biology. doi:10.1186/gb-2007-8-9-227. 
  16. ^ Martins RP, Ostermeier GC, Krawetz SA (December 2004). "Nuclear matrix interactions at the human protamine domain: a working model of potentiation". J. Biol. Chem. 279 (50): 51862–8. doi:10.1074/jbc.M409415200. PMID 15452126. 
  17. ^ Vilfan ID, Conwell CC, Hud NV (May 2004). "Formation of native-like mammalian sperm cell chromatin with folded bull protamine". J. Biol. Chem. 279 (19): 20088–95. doi:10.1074/jbc.M312777200. PMID 14990583. 
  18. ^ Biegeleisen K (August 2006). "The probable structure of the protamine-DNA complex". J. Theor. Biol. 241 (3): 533–40. doi:10.1016/j.jtbi.2005.12.015. PMID 16442565. 

External links[edit]