Protamine

Last updated
Protamine 1
Identifiers
Symbol PRM1
NCBI gene 5619
HGNC 9447
OMIM 182880
RefSeq NM_002761
UniProt P04553
Other data
Locus Chr. 16 p13.13
Search for
Structures Swiss-model
Domains InterPro
Protamine 2
Identifiers
Symbol PRM2
NCBI gene 5620
HGNC 9448
OMIM 182890
RefSeq NM_002762
UniProt P04554
Other data
Locus Chr. 16 p13.13
Search for
Structures Swiss-model
Domains InterPro

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, part of the sperm's genome is packaged by histones (10-15% in humans and other primates) thought to bind genes that are essential for early embryonic development. [1]

Contents

Protamine and protamine-like (PL) proteins are collectively known as the sperm-specific nuclear basic proteins (SNBPs). The PL proteins are intermediate in structure between protamine and Histone H1. The C-terminal domain of PL could be the precursor of vertebrate protamine. [2]

Spermatogenesis

Alterations to the epigenome post-fertilization. The upper part of the image shows replacement of protamines with histones in paternal pronucleus shortly after fertilization. DNA packaged with protamines forms toroid-shaped structures, shown at the top left corner of the image. Dynamic alterations in the paternal epigenetic landscape following fertilization F1.jpg
Alterations to the epigenome post-fertilization. The upper part of the image shows replacement of protamines with histones in paternal pronucleus shortly after fertilization. DNA packaged with protamines forms toroid-shaped structures, shown at the top left corner of the image.

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. [4] 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. [5]

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. [6] 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. [7]

Medical uses

When mixed with insulin, protamines slow down the onset and increase the duration of insulin action (see NPH insulin). [8]

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. [9]

Protamine sulfate is an antidote for heparin overdose, but severe allergy may occur. [10] 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, [11] but the actual effective peptide portion VSRRRRRRGGRRRR has since been isolated. [12] An analogue of this peptide has also been produced. [13]

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 [14] and nonviral (e.g. utilizing cationic liposomes) [15] 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. [16]

Species distribution and isoforms

Mice, humans [1] and certain fish have two or more different protamines, whereas the sperm of bull and boar, [17] have one form of protamine due to a mutation in the PRM2 gene. In the rat, although the gene for PRM2 is present, expression of this protein is extremely small because of limited transcription due to an inefficient promoter in addition to altered processing of the mRNA transcript. [18]

Mammals

The 2 human protamines are denoted PRM1 and PRM2. In mice and humans, PRM1, PRM2, and TNP2 are co-located in a conserved gene cluster. [19]

Eutherian mammals generally have both PRM1 and PRM2. Metatherians on the other hand only have a homolog to P1. [20]

Fish

Examples of protamines from fish are:

Fish protamine are generally shorter than that of mammals, with a higher amount of arginine. [20]

Sequence

Protamine P1
Identifiers
SymbolProtamine_P1
Pfam PF00260
InterPro IPR000221
PROSITE PDOC00047
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Protamine P2
Identifiers
SymbolProtamine_P2
Pfam PF00841
InterPro IPR000492
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Theoretical model of two adjacent salmon protamine molecules (blue) wrapped around and bound within the major groove the DNA helix (white). Protamine binding neutralizes the phosphodiester backbone of DNA, causing it to coil into toroidal structures. Protamine-DNA model.png
Theoretical model of two adjacent salmon protamine molecules (blue) wrapped around and bound within the major groove the DNA helix (white). Protamine binding neutralizes the phosphodiester backbone of DNA, causing it to coil into toroidal structures.

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. [1]

Structure

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. [1]

The exact secondary and tertiary structure of protamine is not known with certainty, but several proposals have been published since the 1970s. [22] [23] [1] [24] [25] [20] [26] The broad consensus is that protamine forms beta strand structures that then crosslink through disulfide bonds (and potentially dityrosine and cysteine-tyrosine bonds). [25] [20] 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. By neutralizing the backbone charge protamine enables the DNA to more tightly coil. [3] [26] The disulfide bonds function to prevent the dissociation of protamine P1 from DNA until the bonds are reduced when the sperm enters the egg. [1] These long protamine polymers may then wrap around the DNA within the major groove. [1] [23]

See also

Related Research Articles

Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in reinforcing the DNA during cell division, preventing DNA damage, and regulating gene expression and DNA replication. During mitosis and meiosis, chromatin facilitates proper segregation of the chromosomes in anaphase; the characteristic shapes of chromosomes visible during this stage are the result of DNA being coiled into highly condensed chromatin.

<span class="mw-page-title-main">Histone</span> Protein family around which DNA winds to form nucleosomes

In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.

<span class="mw-page-title-main">Protein biosynthesis</span> Assembly of proteins inside biological cells

Protein biosynthesis is a core biological process, occurring inside cells, balancing the loss of cellular proteins through the production of new proteins. Proteins perform a number of critical functions as enzymes, structural proteins or hormones. Protein synthesis is a very similar process for both prokaryotes and eukaryotes but there are some distinct differences.

<span class="mw-page-title-main">Post-translational modification</span> Chemical changes in proteins following their translation from mRNA

In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translate mRNA into polypeptide chains, which may then change to form the mature protein product. PTMs are important components in cell signalling, as for example when prohormones are converted to hormones.

<span class="mw-page-title-main">Histone methyltransferase</span> Histone-modifying enzymes

Histone methyltransferases (HMT) are histone-modifying enzymes, that catalyze the transfer of one, two, or three methyl groups to lysine and arginine residues of histone proteins. The attachment of methyl groups occurs predominantly at specific lysine or arginine residues on histones H3 and H4. Two major types of histone methyltranferases exist, lysine-specific and arginine-specific. In both types of histone methyltransferases, S-Adenosyl methionine (SAM) serves as a cofactor and methyl donor group.
The genomic DNA of eukaryotes associates with histones to form chromatin. The level of chromatin compaction depends heavily on histone methylation and other post-translational modifications of histones. Histone methylation is a principal epigenetic modification of chromatin that determines gene expression, genomic stability, stem cell maturation, cell lineage development, genetic imprinting, DNA methylation, and cell mitosis.

<span class="mw-page-title-main">Histone acetyltransferase</span> Enzymes that catalyze acyl group transfer from acetyl-CoA to histones

Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression.

<span class="mw-page-title-main">Histone octamer</span> 8-protein complex forming the core of nucleosomes

In molecular biology, a histone octamer is the eight-protein complex found at the center of a nucleosome core particle. It consists of two copies of each of the four core histone proteins. The octamer assembles when a tetramer, containing two copies of H3 and two of H4, complexes with two H2A/H2B dimers. Each histone has both an N-terminal tail and a C-terminal histone-fold. Each of these key components interacts with DNA in its own way through a series of weak interactions, including hydrogen bonds and salt bridges. These interactions keep the DNA and the histone octamer loosely associated, and ultimately allow the two to re-position or to separate entirely.

A hormone receptor is a receptor molecule that binds to a specific hormone. Hormone receptors are a wide family of proteins made up of receptors for thyroid and steroid hormones, retinoids and Vitamin D, and a variety of other receptors for various ligands, such as fatty acids and prostaglandins. Hormone receptors are of mainly two classes. Receptors for peptide hormones tend to be cell surface receptors built into the plasma membrane of cells and are thus referred to as trans membrane receptors. An example of this is Actrapid. Receptors for steroid hormones are usually found within the protoplasm and are referred to as intracellular or nuclear receptors, such as testosterone. Upon hormone binding, the receptor can initiate multiple signaling pathways, which ultimately leads to changes in the behavior of the target cells.

Protamine sulfate is a medication that is used to reverse the effects of heparin. It is specifically used in heparin overdose, in low molecular weight heparin overdose, and to reverse the effects of heparin during delivery and heart surgery. It is given by injection into a vein. The onset of effects is typically within five minutes.

<span class="mw-page-title-main">Histone H4</span> One of the five main histone proteins involved in the structure of chromatin

Histone H4 is one of the five main histone proteins involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal tail, H4 is involved with the structure of the nucleosome of the 'beads on a string' organization. Histone proteins are highly post-translationally modified. Covalently bonded modifications include acetylation and methylation of the N-terminal tails. These modifications may alter expression of genes located on DNA associated with its parent histone octamer. Histone H4 is an important protein in the structure and function of chromatin, where its sequence variants and variable modification states are thought to play a role in the dynamic and long term regulation of genes.

<span class="mw-page-title-main">Methyltransferase</span> Group of methylating enzymes

Methyltransferases are a large group of enzymes that all methylate their substrates but can be split into several subclasses based on their structural features. The most common class of methyltransferases is class I, all of which contain a Rossmann fold for binding S-Adenosyl methionine (SAM). Class II methyltransferases contain a SET domain, which are exemplified by SET domain histone methyltransferases, and class III methyltransferases, which are membrane associated. Methyltransferases can also be grouped as different types utilizing different substrates in methyl transfer reactions. These types include protein methyltransferases, DNA/RNA methyltransferases, natural product methyltransferases, and non-SAM dependent methyltransferases. SAM is the classical methyl donor for methyltransferases, however, examples of other methyl donors are seen in nature. The general mechanism for methyl transfer is a SN2-like nucleophilic attack where the methionine sulfur serves as the leaving group and the methyl group attached to it acts as the electrophile that transfers the methyl group to the enzyme substrate. SAM is converted to S-Adenosyl homocysteine (SAH) during this process. The breaking of the SAM-methyl bond and the formation of the substrate-methyl bond happen nearly simultaneously. These enzymatic reactions are found in many pathways and are implicated in genetic diseases, cancer, and metabolic diseases. Another type of methyl transfer is the radical S-Adenosyl methionine (SAM) which is the methylation of unactivated carbon atoms in primary metabolites, proteins, lipids, and RNA.

<span class="mw-page-title-main">ADP-ribosylation</span> Addition of one or more ADP-ribose moieties to a protein.

ADP-ribosylation is the addition of one or more ADP-ribose moieties to a protein. It is a reversible post-translational modification that is involved in many cellular processes, including cell signaling, DNA repair, gene regulation and apoptosis. Improper ADP-ribosylation has been implicated in some forms of cancer. It is also the basis for the toxicity of bacterial compounds such as cholera toxin, diphtheria toxin, and others.

<span class="mw-page-title-main">IGFBP7</span> Protein-coding gene in the species Homo sapiens

Insulin-like growth factor-binding protein 7 is a protein that in humans is encoded by the IGFBP7 gene. The major function of the protein is the regulation of availability of insulin-like growth factors (IGFs) in tissue as well as in modulating IGF binding to its receptors. IGFBP7 binds to IGF with low affinity compared to IGFBPs 1-6. It also stimulates cell adhesion. The protein is implicated in some cancers.

<span class="mw-page-title-main">NASP (gene)</span> Protein-coding gene in the species Homo sapiens

Nuclear autoantigenic sperm protein is a protein that in humans is encoded by the NASP gene. Multiple isoforms are encoded by transcript variants of this gene.

<span class="mw-page-title-main">LUC7L3</span> Protein-coding gene in the species Homo sapiens

LUC7 like 3 pre-mRNA splicing factor (LUC7L3), also known as Cisplatin resistance-associated overexpressed protein, or CROP, is a human gene.

<span class="mw-page-title-main">TNP1</span> Protein-coding gene in the species Homo sapiens

Spermatid nuclear transition protein 1 is a protein that in humans is encoded by the TNP1 gene.

<span class="mw-page-title-main">TNP2</span> Protein-coding gene in the species Homo sapiens

Nuclear transition protein 2 is a protein that in humans is encoded by the TNP2 gene.

<span class="mw-page-title-main">Tudor domain</span>

In molecular biology, a Tudor domain is a conserved protein structural domain originally identified in the Tudor protein encoded in Drosophila. The Tudor gene was found in a Drosophila screen for maternal factors that regulate embryonic development or fertility. Mutations here are lethal for offspring, inspiring the name Tudor, as a reference to the Tudor King Henry VIII and the several miscarriages experienced by his wives.

<span class="mw-page-title-main">AT-hook</span>

The AT-hook is a DNA-binding motif present in many proteins, including the high mobility group (HMG) proteins, DNA-binding proteins from plants and hBRG1 protein, a central ATPase of the human switching/sucrose non-fermenting (SWI/SNF) remodeling complex.

<span class="mw-page-title-main">PRM2</span> Protein-coding gene in the species Homo sapiens

Protamine 2 is a protein that in humans is encoded by the PRM2 gene.

References

  1. 1 2 3 4 5 6 7 Balhorn R (2007). "The protamine family of sperm nuclear proteins". Genome Biology. 8 (9): 227. doi: 10.1186/gb-2007-8-9-227 . PMC   2375014 . PMID   17903313.
  2. ↑ Eirín-López JM, Ausió J (October 2009). "Origin and evolution of chromosomal sperm proteins". BioEssays. 31 (10): 1062–70. doi:10.1002/bies.200900050. PMID   19708021. S2CID   17131119.
  3. 1 2 Jenkins TG, Carrell DT (2012). "Dynamic alterations in the paternal epigenetic landscape following fertilization". Frontiers in Genetics. 3: 143. doi: 10.3389/fgene.2012.00143 . PMC   3442791 . PMID   23024648.
  4. ↑ Brewer LR, Corzett M, Balhorn R (October 1999). "Protamine-induced condensation and decondensation of the same DNA molecule". Science. 286 (5437): 120–3. doi:10.1126/science.286.5437.120. PMID   10506559.
  5. ↑ Woop M (January 2015). "Optimizing Tethered Particle Motion to Measure DNA Compaction by Protamine". Biophysical Journal. 108 (2): 393a. Bibcode:2015BpJ...108..393W. doi: 10.1016/j.bpj.2014.11.2156 .
  6. ↑ Lüke L, Campbell P, Varea Sánchez M, Nachman MW, Roldan ER (May 2014). "Sexual selection on protamine and transition nuclear protein expression in mouse species". Proceedings. Biological Sciences. 281 (1783): 20133359. doi:10.1098/rspb.2013.3359. PMC   3996607 . PMID   24671975.
  7. ↑ Wyckoff GJ, Wang W, Wu CI (January 2000). "Rapid evolution of male reproductive genes in the descent of man". Nature. 403 (6767): 304–9. Bibcode:2000Natur.403..304W. doi:10.1038/35002070. PMID   10659848. S2CID   3136139.
  8. ↑ Owens DR (June 2011). "Insulin preparations with prolonged effect". Diabetes Technology & Therapeutics. 13 (Suppl 1): S5-14. doi:10.1089/dia.2011.0068. PMID   21668337.
  9. ↑ Carr JA, Silverman N (October 1999). "The heparin-protamine interaction. A review". The Journal of Cardiovascular Surgery. 40 (5): 659–66. PMID   10596998.
  10. ↑ Weiler JM, Freiman P, Sharath MD, Metzger WJ, Smith JM, Richerson HB, et al. (February 1985). "Serious adverse reactions to protamine sulfate: are alternatives needed?". The Journal of Allergy and Clinical Immunology. 75 (2): 297–303. doi:10.1016/0091-6749(85)90061-2. PMID   2857186.
  11. ↑ 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 Journal. 46 (4): 435–9. doi: 10.1097/00002480-200007000-00013 . PMID   10926141. S2CID   13106365.
  12. ↑ He H, Ye J, Liu E, Liang Q, Liu Q, Yang VC (November 2014). "Low molecular weight protamine (LMWP): a nontoxic protamine substitute and an effective cell-penetrating peptide". Journal of Controlled Release. 193: 63–73. doi:10.1016/j.jconrel.2014.05.056. PMID   24943246.
  13. ↑ Chang LC, Lee HF, Yang Z, Yang VC (1 September 2001). "Low molecular weight protamine (LMWP) as nontoxic heparin/low molecular weight heparin antidote (I): preparation and characterization". AAPS PharmSci. 3 (3): 7–14. doi:10.1208/ps030317. PMC   2751012 . PMID   11741268.
  14. ↑ Cornetta K, Anderson WF (February 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): 187–94. doi:10.1016/0166-0934(89)90132-8. PMID   2786000.
  15. ↑ Sorgi FL, Bhattacharya S, Huang L (September 1997). "Protamine sulfate enhances lipid-mediated gene transfer". Gene Therapy. 4 (9): 961–8. doi: 10.1038/sj.gt.3300484 . PMID   9349433. S2CID   22101764.
  16. ↑ Duarte-Vázquez MA, García-Padilla S, Olvera-Ochoa L, González-Romero KE, Acosta-Iñiguez J, De la Cruz-Cordero R, Rosado JL (June 2009). "Effect of protamine in obesity induced by high-fat diets in rats". International Journal of Obesity. 33 (6): 687–92. doi:10.1038/ijo.2009.78. PMID   19434066. S2CID   22589323.
  17. ↑ Maier WM, Nussbaum G, Domenjoud L, Klemm U, Engel W (March 1990). "The lack of protamine 2 (P2) in boar and bull spermatozoa is due to mutations within the P2 gene". Nucleic Acids Research. 18 (5): 1249–54. doi:10.1093/nar/18.5.1249. PMC   330441 . PMID   2320417.
  18. ↑ Bunick D, Balhorn R, Stanker LH, Hecht NB (May 1990). "Expression of the rat protamine 2 gene is suppressed at the level of transcription and translation". Experimental Cell Research. 188 (1): 147–52. doi:10.1016/0014-4827(90)90290-q. PMID   2328773.
  19. ↑ Wykes SM, Krawetz SA (October 2003). "Conservation of the PRM1 → PRM2 → TNP2 domain". DNA Sequence. 14 (5): 359–67. doi:10.1080/10425170310001599453. PMID   14756422. S2CID   37737173.
  20. 1 2 3 4 Powell CD, Kirchoff DC, DeRouchey JE, Moseley HN (April 2020). "Entropy based analysis of vertebrate sperm protamines sequences: evidence of potential dityrosine and cysteine-tyrosine cross-linking in sperm protamines". BMC Genomics. 21 (1): 277. doi: 10.1186/s12864-020-6681-2 . PMC   7126135 . PMID   32245406.
  21. ↑ Balhorn R (2007-09-26). "The protamine family of sperm nuclear proteins". Genome Biology. 8 (9): 227. doi: 10.1186/gb-2007-8-9-227 . PMC   2375014 . PMID   17903313.
  22. ↑ Warrant RW, Kim SH (January 1978). "alpha-Helix-double helix interaction shown in the structure of a protamine-transfer RNA complex and a nucleoprotamine model". Nature. 271 (5641): 130–5. Bibcode:1978Natur.271..130W. doi:10.1038/271130a0. PMID   622153. S2CID   4172929.
  23. 1 2 Hud NV, Milanovich FP, Balhorn R (June 1994). "Evidence of novel secondary structure in DNA-bound protamine is revealed by Raman spectroscopy". Biochemistry. 33 (24): 7528–35. doi:10.1021/bi00190a005. PMID   8011618.
  24. ↑ Martins RP, Ostermeier GC, Krawetz SA (December 2004). "Nuclear matrix interactions at the human protamine domain: a working model of potentiation". The Journal of Biological Chemistry. 279 (50): 51862–8. doi: 10.1074/jbc.M409415200 . PMID   15452126.
  25. 1 2 Vilfan ID, Conwell CC, Hud NV (May 2004). "Formation of native-like mammalian sperm cell chromatin with folded bull protamine". The Journal of Biological Chemistry. 279 (19): 20088–95. doi: 10.1074/jbc.M312777200 . PMID   14990583.
  26. 1 2 Ukogu OA, Smith AD, Devenica LM, Bediako H, McMillan RB, Ma Y, et al. (June 2020). "Protamine loops DNA in multiple steps". Nucleic Acids Research. 48 (11): 6108–6119. doi:10.1093/NAR/GKAA365. PMC   7293030 . PMID   32392345.
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