Proline isomerization in epigenetics

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In epigenetics, proline isomerization is the effect that cis-trans isomerization of the amino acid proline has on the regulation of gene expression. Similar to aspartic acid, the amino acid proline has the rare property of being able to occupy both cis and trans isomers of its prolyl peptide bonds with ease. Peptidyl-prolyl isomerase, or PPIase, is an enzyme very commonly associated with proline isomerization due to their ability to catalyze the isomerization of prolines. PPIases are present in three types: cyclophilins, FK507-binding proteins, and the parvulins. [1] PPIase enzymes catalyze the transition of proline between cis and trans isomers and are essential to the numerous biological functions controlled and affected by prolyl isomerization (i.e. cell signalling, protein folding, and epigenetic modifications) [2] Without PPIases, prolyl peptide bonds will slowly switch between cis and trans isomers, a process that can lock proteins in a nonnative structure that can affect render the protein temporarily ineffective. Although this switch can occur on its own, PPIases are responsible for most isomerization of prolyl peptide bonds. The specific amino acid that precedes the prolyl peptide bond also can have an effect on which conformation the bond assumes. For instance, when an aromatic amino acid is bonded to a proline the bond is more favorable to the cis conformation. Cyclophilin A uses an "electrostatic handle" to pull proline into cis and trans formations. [3] Most of these biological functions are affected by the isomerization of proline when one isomer interacts differently than the other, commonly causing an activation/deactivation relationship. As an amino acid, proline is present in many proteins. This aids in the multitude of effects that isomerization of proline can have in different biological mechanisms and functions.

Contents

Cell signaling

Cell signaling involves many different processes and proteins. One of the most studied cell signaling phenomena involving proline is the interactions with p53 and prolyl isomerases, specifically Pin1. The protein p53, along with p63 and p73, are responsible for ensuring that alterations to the genome are corrected and for preventing the formation and growth of tumors. proline residues are found throughout the p53 proteins and without the phosphorylation and isomerization of specific Serine/Threonine-Proline motifs within p53, they cannot exhibit control over their target genes. The main signalling processes that are affected by p53 are apoptosis and cell cycle arrest, both of which are controlled by specific isomerization of the prolines in p53. [4]

History and discovery

Although isomerization of proteins has been known about since 1968 when it was discovered by C. Tanford, proline isomerization and its use as a noncovalent histone tail modification was not discovered until 2006 by Nelson and his colleagues. [1] [5]

As a histone tail modification

One of the most well known epigenetic mechanisms that proline isomerization plays a role in is the modification of histone tails, specifically those of histone H3. Fpr4 is a PPIase, in the FK507BP group, that exhibits catalytic activity at the proline positions 16, 30, and 38 (also written P16, P30, and P38 respectively) on the N-terminal region of histone H3 in Saccharomyces cerevisiae . [1] [5] [6] Fpr4's binding affinity is strongest at the P38 site, followed by P30 and then P16. However the catalytic efficiency, or the increase in isomerization rates, is highest at P16 and P30 equally, followed by P38 which exhibits a very small change in isomerization rates with the binding of Fpr4. [6] Histone H3 has an important lysine residue at the 36 position (also written K36) on the N-terminal tail which can be methylated by Set2, a methyltransferase. Methylation of K36 is key to normal transcription elongation. [5] Due to P38's proximity to K36, cross-talk between P38 isomerization and K36 methylation can occur. [1] [5] [7] This means that isomer changes at the P38 position can affect methylation at the K36 position. In the cis position, P38 shifts the histone tail closer to the DNA, crowding the area around the tail. This can cause a decrease the ability of proteins to bind to the DNA and to the histone tail, including preventing Set2 from methylating K36. Also, this tail movement can increase the number interactions between the histone tail and the DNA, increasing likelihood of nucleosome formation and potentially leading to the creation of higher-order chromatin structure. In trans, P38 leads to the opposite effects: allowing for Set2 to methylate K36. Set2 is only affected by isomerization of P38 when creating a trimethylated K36 (commonly written as K36me3), however, and not K36me2. [1] [8] Fpr4 also binds to P32 in H4, though its effects are minimal. [9]

In mammalian cells, the isomerization of H3P30 interacts with the phosphorylation of H3S28 (serine in the 28 position of histone H3) and the methylation of H3K27. [1] [7] hFKBP25 is a PPIase that is a homolog for Fpr4 in mammalian cells and is found to commonly be associated with the presence of HDACs. Cyp33 is a cyclophilin that has the ability to isomerize H3 proline residues at P16 and P30 positions. [9] [10] Histones H2A and H2B also have multiple proline residues near amino acids that when modified affect the activity surrounding the histone.

Interactions with H3K4me3 and H3K14ac

The isomerization of the peptide bond between histone H3's alanine 15 and proline 16 is affected by the acetylation at K14 and can control the methylation states of K4. [3] [11] K4me3 represses gene transcription and depends upon the Set1 methyltransferase complex subunit Spp1 being balanced with the Jhd2 demethylases for proper function. Acetylation of K14 allows for a state change in P16 and primarily promotes the trans state of P16. This trans isomer of P16 reduces K4 methylation, which results in transcription repression. [5] [11] Isomerization of P16 has downstream effects of controlling protein binding to acetylated K18. [9] When P16 is in the trans conformation, Spt7 is allowed to bind to K18ac, increasing transcription.

Interactions with gene regulatory proteins

RNA polymerase II

Proline isomerization of certain prolines in RNA polymerase II is key in the process of recruiting and placing processing factors during transcription. [12] PPIases target RNA polymerase II by interacting with the Rpb1 carboxy terminal domain, or CTD. [9] [12] Proline isomerization is then used as part of the mechanism of the CTD to recruit co-factors required for co-transcriptional RNA processing, regulating RNA polymerase II activity. Nrd1 is a protein that is responsible for many of the transcriptional activities of RNAP II, specifically through the Nrd1- dependent termination pathway. [12] This pathway requires the parvulin Ess1, or Pin1 depending on the organism, to isomerize the pSer5-Pro6 bond in the CTD. Without the cis conformation of the pSer5-Pro6 bond, created by Ess1/Pin1, Nrd1 cannot bind to RNAP II. Any variation from this process leads to a decrease in Nrd1 binding affinity, lowering the ability of RNAP II to process and degrade noncoding RNAs.

MLL1

Cyp33 in mammals causes isomerization in MLL1. [13] MLL1 is a multiprotein complex that regulates gene expression and chromosomal translocations involving this gene often lead to leukemia. [10] MLL's target genes include HOXC8, HOXA9, CDKN1B, and C-MYC. MLL also has two binding domains: a Cyp33 RNA-recognition motif domain (RRM), and a PHD3 domain that binds to H3K4me3 or Cyp33 RRM. Cyp33 has the ability to downregulate the expression of these genes through proline isomerization at the peptide bond between His1628 and Pro1629 within MLL. [13] This bond lies in a sequence between the PHD3 finger of MLL1 and the bromeodomain of MLL1, and its isomerization mediates the bonding of the PHD3 domain and the Cyp33 RRM domain. When these two domains are bonded transcription is repressed through recruitment of histone deacetylases to MLL1 and inhibition of H3K4me3. [9] [13]

Phosphatase recruitment

Phosphorylated amino acids are crucial for the modulation of the binding of transcription factors and other gene regulatory proteins. Pin1's effect on isomerization of proline residues leads to an increase or decrease in recruitment of phosphatases, namely Scp1 and Ssu72 and their recruitment to the RNAP II CTD. [13] The cis-Pro formation is associated with an increase in Ssu72. Scp1 on recognizes trans-Pro formations, and is not affected by such isomerization. Pin1 also triggers the activation of the DSIF complex and NELF, which are responsible for pausing RNAP II in mammalian cells, and their conversion into positive elongation factors, facilitating elongation. [9] This potentially could be an isomerization dependent process.

Regulation of mRNA stability

Pin1, a parvulin, regulates mRNA stability and expression in certain eukaryotics mRNAs. [13] These mRNAs are GM-CSF, Pth, and TGFβ and each of them have AREs, or AU-rich cis-elements. The ARE binding protein KSRP has a Pin1 binding site. Pin1 binds to this site and dephosphorylates the serine and isomerizes the peptide bond between Ser181 and Pro182. This isomerization causes the decay of Pth mRNA. KSRP, and other ARE binding proteins like AUF1, are thought to affect the other mRNAs through mechanisms similar to Pth, with the requirement of a phosphorylated serine bonded to a proline in a specific conformation. Pin1 also triggers proline isomerization of Stem-Loop Binding Protein (SLBP), allowing it to control the dissociation of SLBP from histone mRNA. This leads to Pin1 being able to affect histone mRNA decay. Pin1 affects many other genes in the form of gene silencing through the disruption of cell pathways, making it important in mRNA turnover by modulating RNA binding protein activity.

Difficulties with research

Currently there are no existing compounds that can mimic the peptide bond of proline to other amino acids while maintaining only a cis or trans configuration because most mimics found will eventually change from one isomer to another. This makes research on the direct effect of each of the isomers on biological mechanisms more difficult. [14] Also, the actual isomerization of proline is a slow process, meaning that any studying of the effects of the different isomers of proline takes a large amount of time to complete. [15]

Related Research Articles

<span class="mw-page-title-main">Peptide bond</span> Covalent chemical bond between amino acids in a peptide or protein chain

In organic chemistry, a peptide bond is an amide type of covalent chemical bond linking two consecutive alpha-amino acids from C1 of one alpha-amino acid and N2 of another, along a peptide or protein chain.

Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group -NH
2 but is rather a secondary amine. The secondary amine nitrogen is in the protonated form (NH2+) under biological conditions, while the carboxyl group is in the deprotonated −COO− form. The "side chain" from the α carbon connects to the nitrogen forming a pyrrolidine loop, classifying it as a aliphatic amino acid. It is non-essential in humans, meaning the body can synthesize it from the non-essential amino acid L-glutamate. It is encoded by all the codons starting with CC (CCU, CCC, CCA, and CCG).

A polyproline helix is a type of protein secondary structure which occurs in proteins comprising repeating proline residues. A left-handed polyproline II helix is formed when sequential residues all adopt (φ,ψ) backbone dihedral angles of roughly and have trans isomers of their peptide bonds. This PPII conformation is also common in proteins and polypeptides with other amino acids apart from proline. Similarly, a more compact right-handed polyproline I helix is formed when sequential residues all adopt (φ,ψ) backbone dihedral angles of roughly and have cis isomers of their peptide bonds. Of the twenty common naturally occurring amino acids, only proline is likely to adopt the cis isomer of the peptide bond, specifically the X-Pro peptide bond; steric and electronic factors heavily favor the trans isomer in most other peptide bonds. However, peptide bonds that replace proline with another N-substituted amino acid are also likely to adopt the cis isomer.

In molecular biology, immunophilins are endogenous cytosolic peptidyl-prolyl isomerases (PPI) that catalyze the interconversion between the cis and trans isomers of peptide bonds containing the amino acid proline (Pro). They are chaperone molecules that generally assist in the proper folding of diverse "client" proteins. Immunophilins are traditionally classified into two families that differ in sequence and biochemical characteristics. These two families are: "cyclosporin-binding cyclophilins (CyPs)" and "FK506-binding proteins (FKBPs)". In 2005, a group of dual-family immunophilins (DFI) has been discovered, mostly in unicellular organisms; these DFIs are natural chimera of CyP and FKBPs, fused in either order.

<span class="mw-page-title-main">Prolyl isomerase</span> Enzyme

Prolyl isomerase is an enzyme found in both prokaryotes and eukaryotes that interconverts the cis and trans isomers of peptide bonds with the amino acid proline. Proline has an unusually conformationally restrained peptide bond due to its cyclic structure with its side chain bonded to its secondary amine nitrogen. Most amino acids have a strong energetic preference for the trans peptide bond conformation due to steric hindrance, but proline's unusual structure stabilizes the cis form so that both isomers are populated under biologically relevant conditions. Proteins with prolyl isomerase activity include cyclophilin, FKBPs, and parvulin, although larger proteins can also contain prolyl isomerase domains.

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

Parvulin, a 92-amino acid protein discovered in E. coli in 1994, is the smallest known protein with prolyl isomerase activity, which catalyzes the cis-trans isomerization of proline peptide bonds. Although parvulin has no homology with larger prolyl isomerases such as cyclophilin and FKBP, it does share structural features with subdomains of other proteins involved in preparing secreted proteins for export from the cell.

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

Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core histone proteins, which then join to form nucleosomes. These nucleosomes further fold together into highly condensed chromatin, which renders the organism's genetic material far less accessible to the factors required for gene transcription, DNA replication, recombination and repair. Subsequently, eukaryotic organisms have developed intricate mechanisms to overcome this repressive barrier imposed by the chromatin through histone modification, a type of post-translational modification which typically involves covalently attaching certain groups to histone residues. Once added to the histone, these groups elicit either a loose and open histone conformation, euchromatin, or a tight and closed histone conformation, heterochromatin. Euchromatin marks active transcription and gene expression, as the light packing of histones in this way allows entry for proteins involved in the transcription process. As such, the tightly packed heterochromatin marks the absence of current gene expression.

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

Peptidylprolyl isomerase A (PPIA), also known as cyclophilin A (CypA) or rotamase A is an enzyme that in humans is encoded by the PPIA gene on chromosome 7. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to regulate many biological processes, including intracellular signaling, transcription, inflammation, and apoptosis. Due to its various functions, PPIA has been implicated in a broad range of inflammatory diseases, including atherosclerosis and arthritis, and viral infections.

<span class="mw-page-title-main">SUV39H1</span> Protein-coding gene in the species Homo sapiens

Histone-lysine N-methyltransferase SUV39H1 is an enzyme that in humans is encoded by the SUV39H1 gene.

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

Peptidyl-prolyl cis-trans isomerase B is an enzyme that is encoded by the PPIB gene. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to regulate protein folding of type I collagen. Generally, PPIases are found in all eubacteria and eukaryotes, as well as in a few archaebacteria, and thus are highly conserved.

<span class="mw-page-title-main">PIN1</span> Protein-coding gene in the species Homo sapiens

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 is an enzyme that in humans is encoded by the PIN1 gene.

<span class="mw-page-title-main">FKBP3</span> Protein-coding gene in the species Homo sapiens

FK506-binding protein 3 also known as FKBP25 is a protein that in humans is encoded by the FKBP3 gene.

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

Peptidylprolyl isomerase D (cyclophilin D), also known as PPID, is an enzyme which in humans is encoded by the PPID gene on chromosome 4. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to facilitate folding or repair of proteins. In addition, PPID participates in many biological processes, including mitochondrial metabolism, apoptosis, redox, and inflammation, as well as in related diseases and conditions, such as ischemic reperfusion injury, AIDS, and cancer.

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

Peptidyl-prolyl cis-trans isomerase, mitochondrial (PPIF) is an enzyme that in humans is encoded by the PPIF gene. It has also been referred to as, but should not be confused with, cyclophilin D (CypD), which is encoded by the PPID gene. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to facilitate folding or repair of proteins. PPIF is a major component of the mitochondrial permeability transition pore (MPTP) and, thus, highly involved in mitochondrial metabolism and apoptosis, as well as in mitochondrial diseases and related conditions, including cardiac diseases, neurodegenerative diseases, and muscular dystrophy. In addition, PPIF participates in inflammation, as well as in ischemic reperfusion injury, AIDS, and cancer.

<span class="mw-page-title-main">PPIL1</span> Protein-coding gene in the species Homo sapiens

Peptidyl-prolyl cis-trans isomerase-like 1 is an enzyme that in humans is encoded by the PPIL1 gene.

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

Peptidyl-prolyl cis-trans isomerase H is an enzyme that in humans is encoded by the PPIH gene.

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

Peptidyl-prolyl cis-trans isomerase C (PPIC) is an enzyme that in humans is encoded by the PPIC gene on chromosome 5. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to facilitate folding or repair of proteins. In addition, PPIC participates in many biological processes, including mitochondrial metabolism, apoptosis, redox, and inflammation, as well as in related diseases and conditions, such as ischemic reperfusion injury, AIDS, and cancer.

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

Peptidylprolyl isomerase E (cyclophilin E), also known as PPIE, is an enzyme which in humans is encoded by the PPIE gene on chromosome 1. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, which allows it to facilitate folding or repair of proteins. In addition, PPIE participates in many biological processes, including mitochondrial metabolism, apoptosis, and inflammation, as well as related diseases and conditions, such as ischemic reperfusion injury, AIDS, influenza, and cancer.

Protein methylation is a type of post-translational modification featuring the addition of methyl groups to proteins. It can occur on the nitrogen-containing side-chains of arginine and lysine, but also at the amino- and carboxy-termini of a number of different proteins. In biology, methyltransferases catalyze the methylation process, activated primarily by S-adenosylmethionine. Protein methylation has been most studied in histones, where the transfer of methyl groups from S-adenosyl methionine is catalyzed by histone methyltransferases. Histones that are methylated on certain residues can act epigenetically to repress or activate gene expression.

Par14 is a member of the parvulin family of peptidyl-prolyl-cis/trans-isomerases (PPIases) in humans, which possesses prolyl isomerase activity.

References

  1. 1 2 3 4 5 6 Sadakierska-Chudy, Anna; Filip, Małgorzata (2015). "A Comprehensive View of the Epigenetic Landscape. Part II: Histone Post-translational Modification, Nucleosome Level, and Chromatin Regulation by ncRNAs". Neurotoxicity Research. 27 (2): 172–197. doi:10.1007/s12640-014-9508-6. ISSN   1029-8428. PMC   4300421 . PMID   25516120.
  2. ↑ Follis, Ariele Viacava; Llambi, Fabien; Merritt, Parker; Chipuk, Jerry E.; Green, Douglas R.; Kriwacki, Richard W. (August 2015). "Pin1-Induced Proline Isomerization in Cytosolic p53 Mediates BAX Activation and Apoptosis". Molecular Cell. 59 (4): 677–684. doi:10.1016/j.molcel.2015.06.029. ISSN   1097-2765. PMC   4546541 . PMID   26236013.
  3. 1 2 Osamor, Victor Chukwudi; Chinedu, Shalom N; Azuh, Dominic E; Iweala, Emeka Joshua; Ogunlana, Olubanke Olujoke (2016-02-29). "The interplay of post-translational modification and gene therapy". Drug Design, Development and Therapy. 10: 861–871. doi: 10.2147/DDDT.S80496 . ISSN   1177-8881. PMC   4778776 . PMID   27013864.
  4. ↑ Mantovani, Fiamma; Zannini, Alessandro; Rustighi, Alessandra; del sal, Giannino (2015-01-29). "Interaction of p53 with prolyl isomerases: Healthy and unhealthy relationships". Biochimica et Biophysica Acta (BBA) - General Subjects. 1850 (10): 2048–2060. doi:10.1016/j.bbagen.2015.01.013. PMID   25641576.
  5. 1 2 3 4 5 Tollefsbol, Trygve (2017-07-10). Handbook of epigenetics : the new molecular and medical genetics. Tollefsbol, Trygve O. (Second ed.). London, United Kingdom. ISBN   9780128054772. OCLC   993671596.{{cite book}}: CS1 maint: location missing publisher (link)
  6. 1 2 Monneau, Yoan R.; Soufari, Heddy; Nelson, Christopher J.; Mackereth, Cameron D. (2013-09-06). "Structure and Activity of the Peptidyl-Prolyl Isomerase Domain from the Histone Chaperone Fpr4 toward Histone H3 Proline Isomerization". The Journal of Biological Chemistry. 288 (36): 25826–25837. doi: 10.1074/jbc.M113.479964 . ISSN   0021-9258. PMC   3764789 . PMID   23888048.
  7. 1 2 Nelson, Christopher J.; Santos-Rosa, Helena; Kouzarides, Tony (September 2006). "Proline Isomerization of Histone H3 Regulates Lysine Methylation and Gene Expression". Cell. 126 (5): 905–916. doi: 10.1016/j.cell.2006.07.026 . ISSN   0092-8674. PMID   16959570. S2CID   17789997.
  8. ↑ Youdell, Michael L.; Kizer, Kelby O.; Kisseleva-Romanova, Elena; Fuchs, Stephen M.; Duro, Eris; Strahl, Brian D.; Mellor, Jane (August 2008). "Roles for Ctk1 and Spt6 in Regulating the Different Methylation States of Histone H3 Lysine 36". Molecular and Cellular Biology. 28 (16): 4915–4926. doi:10.1128/MCB.00001-08. ISSN   0270-7306. PMC   2519698 . PMID   18541663.
  9. 1 2 3 4 5 6 Hanes, Steven D. (2015-10-01). "Prolyl isomerases in gene transcription". Biochimica et Biophysica Acta (BBA) - General Subjects. 1850 (10): 2017–2034. doi:10.1016/j.bbagen.2014.10.028. ISSN   0304-4165. PMC   4417086 . PMID   25450176.
  10. 1 2 Park, Sangho; Osmers, Ute; Raman, Gayathree; Schwantes, Rebecca H.; Diaz, Manuel O.; Bushweller, John H. (2010-08-10). "The PHD3 Domain of MLL Acts as a CYP33-Regulated Switch between MLL-Mediated Activation and Repression". Biochemistry. 49 (31): 6576–6586. doi:10.1021/bi1009387. ISSN   0006-2960. PMC   2916634 . PMID   20677832.
  11. 1 2 Howe, Françoise S.; Boubriak, Ivan; Sale, Matthew J.; Nair, Anitha; Clynes, David; Grijzenhout, Anne; Murray, Struan C.; Woloszczuk, Ronja; Mellor, Jane (2014-09-04). "Lysine Acetylation Controls Local Protein Conformation by Influencing Proline Isomerization". Molecular Cell. 55 (5): 733–744. doi:10.1016/j.molcel.2014.07.004. ISSN   1097-2765. PMC   4157579 . PMID   25127513.
  12. 1 2 3 Kubicek, Karel; Cerna, Hana; Holub, Peter; Pasulka, Josef; Hrossova, Dominika; Loehr, Frank; Hofr, Ctirad; Vanacova, Stepanka; Stefl, Richard (2012-09-01). "Serine phosphorylation and proline isomerization in RNAP II CTD control recruitment of Nrd1". Genes & Development. 26 (17): 1891–1896. doi:10.1101/gad.192781.112. ISSN   0890-9369. PMC   3435493 . PMID   22892239.
  13. 1 2 3 4 5 Thapar, Roopa (2015-05-18). "Roles of Prolyl Isomerases in RNA-Mediated Gene Expression". Biomolecules. 5 (2): 974–999. doi: 10.3390/biom5020974 . ISSN   2218-273X. PMC   4496705 . PMID   25992900.
  14. ↑ Rob, Oslund. "Analysis of Proline Isomerization in Epigenetics". Grantome.
  15. ↑ Hamelberg, Donald; Shen, Tongye; McCammon, J. Andrew (February 2005). "Phosphorylation Effects on cis/trans Isomerization and the Backbone Conformation of Serine−Proline Motifs: Accelerated Molecular Dynamics Analysis". Journal of the American Chemical Society. 127 (6): 1969–1974. doi:10.1021/ja0446707. ISSN   0002-7863. PMID   15701032.
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