Статті в журналах: "Octapeptide repeat region"

1

Görnhardt, Birgit, Ila Rouhara, and Elmon Schmelzer. "Cyst Germination Proteins of the Potato Pathogen Phytophthora infestans Share Homology with Human Mucins." Molecular Plant-Microbe Interactions® 13, no. 1 (January 2000): 32–42. http://dx.doi.org/10.1094/mpmi.2000.13.1.32.

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We have cloned genes of Phytophthora infestans, the causal agent of potato late blight, that are activated shortly before the onset of invasion of the host tissue. The three genes isolated appear to be arranged in a genomic cluster and belong to a small polymorphic gene family. A conspicuous feature of the deduced proteins is an internal octapeptide repeat with the consensus sequence TTYAP TEE. Because of this structural motif, these novel P. infestans proteins were named Car (cyst-germination-specific acidic repeat) proteins. One of the genes, car90, codes for 1,489 amino acids including 120 octapeptide tandem repeats. Car proteins are transiently expressed during germination of cysts and formation of appressoria and are localized at the surface of germlings. The structural motif of tandemly repeated oligopeptides also occurs in a prominent class of proteins, the mucins, from mammals. The P. infestans Car proteins share 51% sequence homology with the tandem repeat region of a subfamily of human mucins. According to the physiological functions ascribed to mucins, we suggest that Car proteins may serve as a mucous cover protecting the germling from desiccation, physical damage, and adverse effects of the plant defense response and may assist in adhesion to the leaf surface.

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2

Hara, Hideyuki, and Suehiro Sakaguchi. "N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases." International Journal of Molecular Sciences 21, no. 17 (August 28, 2020): 6233. http://dx.doi.org/10.3390/ijms21176233.

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The normal cellular isoform of prion protein, designated PrPC, is constitutively converted to the abnormally folded, amyloidogenic isoform, PrPSc, in prion diseases, which include Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. PrPC is a membrane glycoprotein consisting of the non-structural N-terminal domain and the globular C-terminal domain. During conversion of PrPC to PrPSc, its 2/3 C-terminal region undergoes marked structural changes, forming a protease-resistant structure. In contrast, the N-terminal region remains protease-sensitive in PrPSc. Reverse genetic studies using reconstituted PrPC-knockout mice with various mutant PrP molecules have revealed that the N-terminal domain has an important role in the normal function of PrPC and the conversion of PrPC to PrPSc. The N-terminal domain includes various characteristic regions, such as the positively charged residue-rich polybasic region, the octapeptide repeat (OR) region consisting of five repeats of an octapeptide sequence, and the post-OR region with another positively charged residue-rich polybasic region followed by a stretch of hydrophobic residues. We discuss the normal functions of PrPC, the conversion of PrPC to PrPSc, and the neurotoxicity of PrPSc by focusing on the roles of the N-terminal regions in these topics.

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3

Hreško, Stanislav, and Ľudmila Tkáčiková. "Variation in the coding region of the prion protein gene in Slovak cattle." Acta Veterinaria Hungarica 60, no. 2 (June 1, 2012): 233–43. http://dx.doi.org/10.1556/avet.2012.020.

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This study was conducted to investigate the presence of single nucleotide polymorphisms (SNPs) in the coding region of the bovine prion protein (PrP) gene among healthy and bovine spongiform encephalopathy (BSE-) affected cattle in Slovakia. Denaturing gradient gel electrophoresis (DGGE) and single-strand conformation polymorphism (SSCP) followed by DNA sequencing were used to identify SNPs and variations in octapeptide repeats. Altogether three single nucleotide polymorphisms (g234a, c339t and c576t) and variations in the number of octapeptide repeat units (5 or 6) were found in the analysed part of the prion protein gene. All single nucleotide polymorphisms were silent, causing no amino acid changes. Significant differences (P < 0.05) in the genotype distribution of g234a polymorphism were observed when the homozygous genotype with a mutated allele (caa/caa) was compared to the heterozygous genotype -/cag among healthy and BSE-affected cattle. The homozygous genotype caa/caa was characteristic of the group of BSE-affected cattle. Additionally, the homozygous genotype caa/caa was significant for the group of Simmental crossbreeds among healthy cattle. The allele and genotype distribution of the other polymorphisms was not significantly different among groups of healthy and BSE-affected cattle. The possible influence of a silent mutation on expression of the gene is not clearly determined and needs further investigations.

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4

Pandey, Krishna K., James P. Snyder, Dennis C. Liotta, and Djamaladdin G. Musaev. "Computational Studies of Transition Metal Selectivity of Octapeptide Repeat Region of Prion Protein (PrP)." Journal of Physical Chemistry B 114, no. 2 (January 21, 2010): 1127–35. http://dx.doi.org/10.1021/jp909945e.

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5

Perera, W. S. S., and N. M. Hooper. "Role of the octapeptide repeat region of the prion protein in copper homeostasis and endocytosis." Biochemical Society Transactions 28, no. 5 (October 1, 2000): A347. http://dx.doi.org/10.1042/bst028a347c.

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6

Shiraishi, Noriyuki, Yuriko Ohta, and Morimitsu Nishikimi. "The Octapeptide Repeat Region of Prion Protein Binds Cu(II) in the Redox-Inactive State." Biochemical and Biophysical Research Communications 267, no. 1 (January 2000): 398–402. http://dx.doi.org/10.1006/bbrc.1999.1944.

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7

Das, Nandita Rani, Hironori Miyata, Hideyuki Hara, Junji Chida, Keiji Uchiyama, Kentaro Masujin, Hitomi Watanabe, Gen Kondoh, and Suehiro Sakaguchi. "The N-Terminal Polybasic Region of Prion Protein Is Crucial in Prion Pathogenesis Independently of the Octapeptide Repeat Region." Molecular Neurobiology 57, no. 2 (November 9, 2019): 1203–16. http://dx.doi.org/10.1007/s12035-019-01804-5.

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8

Flechsig, Eckhard, Doron Shmerling, Ivan Hegyi, Alex J. Raeber, Marek Fischer, Antonio Cozzio, Christian von Mering, Adriano Aguzzi, and Charles Weissmann. "Prion Protein Devoid of the Octapeptide Repeat Region Restores Susceptibility to Scrapie in PrP Knockout Mice." Neuron 27, no. 2 (August 2000): 399–408. http://dx.doi.org/10.1016/s0896-6273(00)00046-5.

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9

Sakudo, Akikazu, Deug-chan Lee, Takuya Nishimura, Shuming Li, Shoutaro Tsuji, Toyoo Nakamura, Yoshitsugu Matsumoto, et al. "Octapeptide repeat region and N-terminal half of hydrophobic region of prion protein (PrP) mediate PrP-dependent activation of superoxide dismutase." Biochemical and Biophysical Research Communications 326, no. 3 (January 2005): 600–606. http://dx.doi.org/10.1016/j.bbrc.2004.11.092.

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10

BROWN, David R., Boon-Seng WONG, Farida HAFIZ, Christine CLIVE, Stephen J. HASWELL, and Ian M. JONES. "Normal prion protein has an activity like that of superoxide dismutase." Biochemical Journal 344, no. 1 (November 8, 1999): 1–5. http://dx.doi.org/10.1042/bj3440001.

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We show here that mouse prion protein (PrPC) either as recombinant protein or immunoprecipitated from brain tissue has superoxide dismutase (SOD) activity. SOD activity was also associated with recombinant chicken PrPC confirming the evolutionary conserved phenotype suggested by sequence similarity. Acquisition of copper by PrPC during protein folding endowed SOD activity on the protein but the addition of copper following refolding did not. PrPC dependent SOD activity was abolished by deletion of the octapeptide-repeat region involved in copper binding. These results describe an enzymic function for PrPC consistent with its cellular distribution and suggest it has a direct role in cellular resistance to oxidative stress.

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11

Miura, Takashi, Satoshi Sasaki, Akira Toyama, and Hideo Takeuchi. "Copper Reduction by the Octapeptide Repeat Region of Prion Protein: pH Dependence and Implications in Cellular Copper Uptake†." Biochemistry 44, no. 24 (June 2005): 8712–20. http://dx.doi.org/10.1021/bi0501784.

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12

Yamaguchi, Yoshitaka, Hironori Miyata, Keiji Uchiyama, Akira Ootsuyama, Sachiko Inubushi, Tsuyoshi Mori, Naomi Muramatsu, Shigeru Katamine, and Suehiro Sakaguchi. "Biological and Biochemical Characterization of Mice Expressing Prion Protein Devoid of the Octapeptide Repeat Region after Infection with Prions." PLoS ONE 7, no. 8 (August 21, 2012): e43540. http://dx.doi.org/10.1371/journal.pone.0043540.

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13

Zhao, Hui, Xiao-Yan Wang, Wei Zou, and Ya-Ping Zhang. "Prion protein gene (PRNP) polymorphisms in native Chinese cattle." Genome 53, no. 2 (February 2010): 138–45. http://dx.doi.org/10.1139/g09-087.

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Polymorphisms in four regions of the bovine prion protein gene (PRNP) confer susceptibility to bovine spongiform encephalopathy (BSE). These polymorphisms include a 23-bp insertion/deletion (indel) in the promoter region, a 12-bp indel in intron 1, an octapeptide repeat or 24-bp indel in the open reading frame, and a single nucleotide polymorphism (SNP) in the coding region. In this study, we investigated the frequency distributions of genotypes, alleles, and haplotypes at these indel sites in 349 native Chinese cattle and sequence variants in 50 samples. Our results showed that cattle in southern China have low frequencies of the 12-bp deletion allele and the 23-bp deletion / 12-bp deletion haplotype, which have been suggested to be relevant to BSE susceptibility. Interestingly, a significant difference was observed between BSE-affected cattle and healthy Chinese cattle in the 12-bp indel polymorphism. A total of 14 SNPs were discovered in the coding region of PRNP in Chinese cattle. Three of these SNPs were associated with amino acid changes (K3T, P54S, and S154N). The E211K substitution that was recently reported in the US atypical BSE case was not detected in this study.

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14

Võ, Tuấn Cường, Nguyen Thi Minh Trinh, Hương Giang Lê, Jung-Mi Kang, Won Gi Yoo, Huynh Hong Quang, and Byoung-Kuk Na. "Genetic Diversity of Circumsporozoite Surface Protein of Plasmodium vivax from the Central Highlands, Vietnam." Pathogens 11, no. 10 (October 7, 2022): 1158. http://dx.doi.org/10.3390/pathogens11101158.

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The circumsporozoite surface protein of Plasmodium vivax (PvCSP) plays a critical role in parasite biology. It has been extensively studied as a leading vivax-malaria-vaccine candidate. In this study, the genetic polymorphism and natural selection of pvcsp in P. vivax isolates collected from the Central Highlands, Vietnam were analyzed to understand the genetic structure of the parasite circulating in the endemic area and to provide baseline information for effective vaccine development based on the protein. Only two major alleles, VK210 and VK247, were detected in Vietnamese pvcsp, with VK247 being the predominant one. The N-terminal and C-terminal regions of Vietnamese VK210 and VK247 variants showed a low genetic diversity. Amino acid substitutions, insertions of a single amino acid or octapeptide (ANKKAEDA in VK210 and ANKKAGDA in VK247), and tetrapeptide repeat motifs (GGNA) were the main factors generating genetic diversity in the two regions of the Vietnamese VK210 and VK247 variants. Interestingly, these two regions of Vietnamese pvcsp displayed a unique natural selection pressure distinct from global pvcsp, particularly with the neighboring Southeast Asian pvcsp population. Meanwhile, the central repeat region (CRR) in both the VK210 and VK247 variants showed a high degree of polymorphic characters, caused by varying numbers, types, and combinations of peptide repeat motifs (PRMs) in Vietnamese pvcsp. Highly complicated polymorphic patterns of the CRR were also detected in global pvcsp. These results expand our understanding of the genetic structure of Vietnamese pvcsp and the population dynamics of P. vivax in the Central Highlands, Vietnam.

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15

Wells, Mark A., Graham S. Jackson, Samantha Jones, Laszlo L. P. Hosszu, C. Jeremy Craven, Anthony R. Clarke, John Collinge, and Jonathan P. Waltho. "A reassessment of copper(II) binding in the full-length prion protein." Biochemical Journal 399, no. 3 (October 13, 2006): 435–44. http://dx.doi.org/10.1042/bj20060458.

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It has been shown previously that the unfolded N-terminal domain of the prion protein can bind up to six Cu2+ ions in vitro. This domain contains four tandem repeats of the octapeptide sequence PHGGGWGQ, which, alongside the two histidine residues at positions 96 and 111, contribute to its Cu2+ binding properties. At the maximum metal-ion occupancy each Cu2+ is co-ordinated by a single imidazole and deprotonated backbone amide groups. However two recent studies of peptides representing the octapeptide repeat region of the protein have shown, that at low Cu2+ availability, an alternative mode of co-ordination occurs where the metal ion is bound by multiple histidine imidazole groups. Both modes of binding are readily populated at pH 7.4, while mild acidification to pH 5.5 selects in favour of the low occupancy, multiple imidazole binding mode. We have used NMR to resolve how Cu2+ binds to the full-length prion protein under mildly acidic conditions where multiple histidine co-ordination is dominant. We show that at pH 5.5 the protein binds two Cu2+ ions, and that all six histidine residues of the unfolded N-terminal domain and the N-terminal amine act as ligands. These two sites are of sufficient affinity to be maintained in the presence of millimolar concentrations of competing exogenous histidine. A previously unknown interaction between the N-terminal domain and a site on the C-terminal domain becomes apparent when the protein is loaded with Cu2+. Furthermore, the data reveal that sub-stoichiometric quantities of Cu2+ will cause self-association of the prion protein in vitro, suggesting that Cu2+ may play a role in controlling oligomerization in vivo.

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16

Lee, Deug-chan, Akikazu Sakudo, Chi-kyeong Kim, Takuya Nishimura, Keiichi Saeki, Yoshitsugu Matsumoto, Takashi Yokoyama, Shu G. Chen, Shigeyoshi Itohara, and Takashi Onodera. "Fusion of Doppel to Octapeptide Repeat and N-Terminal Half of Hydrophobic Region of Prion Protein Confers Resistance to Serum Deprivation." Microbiology and Immunology 50, no. 3 (March 2006): 203–9. http://dx.doi.org/10.1111/j.1348-0421.2006.tb03787.x.

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17

Blanchard, David J., Muzaffer Cicek, Jialun Chen та Asim Esen. "Identification of β-Glucosidase Aggregating Factor (BGAF) and Mapping of BGAF Binding Regions on Maize β-Glucosidase". Journal of Biological Chemistry 276, № 15 (28 листопада 2000): 11895–901. http://dx.doi.org/10.1074/jbc.m008872200.

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In certain maize genotypes (nulls), β-glucosidase does not enter the gel and therefore cannot be detected on zymograms. Such genotypes were initially thought to be homozygous for a null allele at theglu1gene. We have shown that a β-glucosidase aggregating factor (BGAF) is responsible for the null phenotype, and it specifically interacts with maize β-glucosidases and forms large insoluble aggregates. To understand the mechanism of the β-glucosidase-BGAF interaction, we constructed chimeric enzymes by domain swapping between the maize β-glucosidase isozymes Glu1 and Gu2, to which BGAF binds, and the sorghum β-glucosidase (dhurrinase) isozyme Dhr1, to which BGAF does not bind. The results of binding assays with 12 different chimeric enzymes showed that an N-terminal region (Glu50-Val145) and an extreme C-terminal region (Phe466-Ala512) together form the BGAF binding site on the enzyme surface. In addition, we purified BGAF, determined its N-terminal sequence, amplified the BGAF cDNA by reverse transcriptase-polymerase chain reaction, expressed it inEscherichia coli, and showed that it encodes a protein whose binding and immunological properties are identical to the native BGAF isolated from maize tissues. A data base search revealed that BGAF is a member of the jasmonite-induced protein family. Interestingly, the deduced BGAF sequence contained an octapeptide sequence (G(P/R)WGGSGG) repeated twice. Each of these repeat units is postulated to be involved in forming a site for binding to maize β-glucosidases and thus provides a plausible explanation for the divalent function of BGAF predicted from binding assays.

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18

Sakudo, Akikazu, Guoying Wu, Takashi Onodera, and Kazuyoshi Ikuta. "Octapeptide repeat region of prion protein (PrP) is required at an early stage for production of abnormal prion protein in PrP-deficient neuronal cell line." Biochemical and Biophysical Research Communications 365, no. 1 (January 2008): 164–69. http://dx.doi.org/10.1016/j.bbrc.2007.10.158.

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19

Murley, Alexander G., Yu Nie, Zoe Golder, Michael John Keogh, Colin Smith, James W. Ironside, and Patrick F. Chinnery. "High-Depth PRNP Sequencing in Brains With Sporadic Creutzfeldt-Jakob Disease." Neurology Genetics 9, no. 1 (January 19, 2023): e200054. http://dx.doi.org/10.1212/nxg.0000000000200054.

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Background and ObjectivesSporadic Creutzfeldt-Jakob disease (sCJD) has established genetic risk factors, but, in contrast to genetic and acquired CJD, the initial trigger for misfolded prion aggregation and spread is not known. In this study, we tested the hypotheses that pathologic somatic variants in the prion genePRNPare increased in sCJD, potentially leading to the seeding of misfolded prion protein.MethodsHigh-depth amplicon-based short read sequencing of thePRNPcoding region was performed on postmortem brain tissue from patients with a clinical and neuropathologic diagnosis of sCJD (n = 142), Alzheimer disease (AD) (n = 51) and controls with no clinical or neuropathologic diagnosis of a neurodegenerative disease (n = 71). Each DNA sample was sequenced twice, including independent PCR amplification, library preparation, and sequencing. We used RePlow to call somatic variants with high sensitivity and specificity and optimal sequence kernel association test to compare variant burden between groups.ResultsTwo sCJD cases had somatic (variant allele frequency 0.5–1%)PRNPvariants not previously identified, but with high in silico predicated pathogenicity. However, the pathogenicity of these variants is uncertain, as both located in the octapeptide repeat region where no point variations have previously been associated with sCJD. There was no overall difference in burden somaticPRNPin sCJD compared with controls and a lower burden compared with Alzheimer disease.DiscussionSomatic variants inPRNPare unlikely to play a major role in sCJD but may contribute to the disease mechanism in a minority of cases.

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20

Valdez, Reginald A., Matthew J. Rock, Anne K. Anderson, and Katherine I. O'Rourke. "Immunohistochemical Detection and Distribution of Prion Protein in a Goat with Natural Scrapie." Journal of Veterinary Diagnostic Investigation 15, no. 2 (March 2003): 157–62. http://dx.doi.org/10.1177/104063870301500210.

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Formalin-fixed, paraffin-embedded tissue sections from a 3-year-old female Angora goat suffering from clinical scrapie were immunostained after hydrated autoclaving using a monoclonal antibody (mAb, F99/97.6.1; IgG1) specific for a conserved epitope on the prion protein. Widespread and prominent deposition of the scrapie isoform of the prion protein (PrPSc) was observed in the brain, brainstem, spinal cord, retina, postganglionic neurons associated with parasympathetic ganglia of myenteric and submucosal plexuses, Peyer's patches, peripheral lymph nodes, and pharyngeal and palatine tonsils. The goat was homozygous for PrP alleles encoding 5 octapeptide repeat sequences in the N-terminal region of the prion protein and isoleucine at codon 142, a genotype associated with high susceptibility and short incubation times in goats. The results of this study indicate that mAb F99/97.6.1 is useful for detection of PrPSc deposition, and this is a specific and reliable immunohistochemical adjunct to histopathology for diagnosis of natural caprine scrapie, although precise determination of the diagnostic sensitivity and specificity of the assay as a diagnostic test for scrapie in goats will require examination of a sufficiently large sample size. As with ovine scrapie, prion protein is widely distributed in the central and peripheral nervous systems, gastrointestinal tract, and lymphoid tissues in natural caprine scrapie.

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21

Kim, Chan-Lan, Ayako Karino, Naotaka Ishiguro, Morikazu Shinagawa, Motoyoshi Sato, and Motohiro Horiuchi. "Cell-surface retention of PrPC by anti-PrP antibody prevents protease-resistant PrP formation." Journal of General Virology 85, no. 11 (November 1, 2004): 3473–82. http://dx.doi.org/10.1099/vir.0.80113-0.

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The C-terminal portion of the prion protein (PrP), corresponding to a protease-resistant core fragment of the abnormal isoform of the prion protein (PrPSc), is essential for prion propagation. Antibodies to the C-terminal portion of PrP are known to inhibit PrPSc accumulation in cells persistently infected with prions. Here it was shown that, in addition to monoclonal antibodies (mAbs) to the C-terminal portion of PrP, a mAb recognizing the octapeptide repeat region in the N-terminal part of PrP that is dispensable for PrPSc formation reduced PrPSc accumulation in cells persistently infected with prions. The 50 % effective dose was as low as ∼1 nM, and, regardless of their epitope specificity, the inhibitory mAbs shared the ability to bind cellular prion protein (PrPC) expressed on the cell surface. Flow cytometric analysis revealed that mAbs that bound to the cell surface during cell culture were not internalized even after their withdrawal from the growth medium. Retention of the mAb–PrPC complex on the cell surface was also confirmed by the fact that internalization was enhanced by treatment of cells with dextran sulfate. These results suggested that anti-PrP mAb antagonizes PrPSc formation by interfering with the regular PrPC degradation pathway.

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22

PAN, Tao, Boon-Seng WONG, Tong LIU, Ruliang LI, Robert B. PETERSEN, and Man-Sun SY. "Cell-surface prion protein interacts with glycosaminoglycans." Biochemical Journal 368, no. 1 (November 15, 2002): 81–90. http://dx.doi.org/10.1042/bj20020773.

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We used ELISA and flow cytometry to study the binding of prion protein PrP to glycosaminoglycans (GAGs). We found that recombinant human PrP (rPrP) binds GAGs including chondroitin sulphate A, chondroitin sulphate B, hyaluronic acid, and heparin. rPrP binding to GAGs occurs via the N-terminus, a region known to bind divalent cations. Additionally, rPrP binding to GAGs is enhanced in the presence of Cu2+ and Zn2+, but not Ca2+ and Mn2+. rPrP binds heparin strongest, and the binding is inhibited by certain heparin analogues, including heparin disaccharide and sulphate-containing monosaccharides, but not by acetylated heparin. Full-length normal cellular prion protein (PrPC), but not N-terminally truncated PrPC species, from human brain bind GAGs in a similar Cu2+/Zn2+-enhanced fashion. We found that GAGs specifically bind to a synthetic peptide corresponding to amino acid residues 23—35 in the N-terminus of rPrP. We further demonstrated that while both wild-type PrPC and an octapeptide-repeat-deleted mutant PrP produced by transfected cells bound heparin at the cell surface, the PrP N-terminal deletion mutant and non-transfectant control failed to bind heparin. Binding of heparin to wild-type PrPC on the cell surface results in a reduction of the level of cell-surface PrPC. These results provide strong evidence that PrPC is a surface receptor for GAGs.

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23

Johnson, Chad, Jody Johnson, Joshua P. Vanderloo, Delwyn Keane, Judd M. Aiken, and Debbie McKenzie. "Prion protein polymorphisms in white-tailed deer influence susceptibility to chronic wasting disease." Journal of General Virology 87, no. 7 (July 1, 2006): 2109–14. http://dx.doi.org/10.1099/vir.0.81615-0.

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The primary sequence of the prion protein affects susceptibility to transmissible spongiform encephalopathies, or prion diseases, in mice, sheep and humans. The Prnp gene sequence of free-ranging, Wisconsin white-tailed deer was determined and the Prnp genotypes of chronic wasting disease (CWD)-positive and CWD-negative deer were compared. Six amino acid changes were identified, two of which were located in pseudogenes. Two alleles, a Q→K polymorphism at codon 226 and a single octapeptide repeat insertion into the pseudogene, have not been reported previously. The predominant alleles – wild-type (Q95, G96 and Q226) and a G96S polymorphism – comprised almost 98 % of the Prnp alleles in the Wisconsin white-tailed deer population. Comparison of the allelic frequencies in the CWD-positive and CWD-negative deer suggested that G96S and a Q95H polymorphism were linked to a reduced susceptibility to CWD. The G96S allele did not, however, provide complete resistance, as a CWD-positive G96S/G96S deer was identified. The G96S allele was also linked to slower progression of the disease in CWD-positive deer based on the deposition of PrPCWD in the obex region of the medulla oblongata. Although the reduced susceptibility of deer with at least one copy of the Q95H or G96S allele is insufficient to serve as a genetic barrier, the presence of these alleles may modulate the impact of CWD on white-tailed deer populations.

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24

Yu, Shuiliang, Shaoman Yin, Chaoyang Li, Poki Wong, Binggong Chang, Fan Xiao, Shin-Chung Kang, et al. "Aggregation of prion protein with insertion mutations is proportional to the number of inserts." Biochemical Journal 403, no. 2 (March 26, 2007): 343–51. http://dx.doi.org/10.1042/bj20061592.

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Mutation in the prion gene, PRNP, accounts for approx. 10–15% of human prion diseases. However, little is known about the mechanisms by which a mutant prion protein (PrP) causes disease. We compared the biochemical properties of a wild-type human prion protein, rPrPC (recombinant wild-type PrP), which has five octapeptide-repeats, with two recombinant human prion proteins with insertion mutations, one with three more octapeptide repeats, rPrP8OR, and the other with five more octapeptide repeats, rPrP10OR. We found that the insertion mutant proteins are more prone to aggregate, and the degree and kinetics of aggregation are proportional to the number of inserts. The octapeptide-repeat and α-helix 1 regions are important in aggregate formation, because aggregation is inhibited with monoclonal antibodies that are specific for epitopes in these regions. We also showed that a small amount of mutant protein could enhance the formation of mixed aggregates that are composed of mutant protein and wild-type rPrPC. Accordingly, rPrP10OR is also more efficient in promoting the aggregation of rPrPC than rPrP8OR. These findings provide a biochemical explanation for the clinical observations that the severity of the disease in patients with insertion mutations is proportional to the number of inserts, and thus have implications for the pathogenesis of inherited human prion disease.

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25

Hooper, Nigel M., David R. Taylor, and Nicole T. Watt. "Mechanism of the metal-mediated endocytosis of the prion protein." Biochemical Society Transactions 36, no. 6 (November 19, 2008): 1272–76. http://dx.doi.org/10.1042/bst0361272.

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The cellular form of the prion protein, PrPc, is critically required for the establishment of prion diseases, such as Creutzfeldt–Jakob disease. Within the N-terminal half of PrPc are four octapeptide repeats that bind Cu2+. Exposure of neuronal cells expressing PrPc to Cu2+ results in the rapid endocytosis of the protein. First, PrPc translocates laterally out of detergent-resistant lipid rafts into detergent-soluble regions of the plasma membrane, then it is internalized through clathrin-coated pits. The extreme N-terminal region of PrPc is critically required for its endocytosis, as is the transmembrane LRP1 (low-density lipoprotein receptor-related protein-1). Incubation of cells with a competitive inhibitor of LRP1 ligands, receptor-associated protein, or down-regulation of LRP1 with siRNA (short interfering RNA) reduces the endocytosis of PrPc. Zn2+ also promotes the endocytosis of PrPc, a phenomenon that is also dependent on the octapeptide repeats and requires LRP1.

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El-Sayed, Amr, Jörg Alber, Christoph Lämmler, Amir Abdulmawjood, Michael Zschöck, and V. Hugo Castañeda. "Comparative sequence analysis of spa gene of Staphylococcus aureus isolated from bovine mastitis: characterization of an unusual spa gene variant." Journal of Dairy Research 73, no. 3 (March 29, 2006): 322–27. http://dx.doi.org/10.1017/s002202990600183x.

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The protein A encoding gene spa of four Staphylococcus aureus strains isolated from bovine clinical mastitis was amplified by PCR and sequenced. The four strains were selected after an initial screening of spa gene of 41 strains isolated from mastitic cows and were subjected to detailed investigations. According to the sequencing results the spa gene of three strains (M1, M2, M3) appeared with gene segments encoding five (E, D, A, B and C) and four (E, A, B and C) IgG binding domains for two (M1, M3) and one (M2) strain, respectively and with gene segments encoding four, two and two repeats of the octapeptide Xr-repeats for the strains M1, M2 and M3, respectively. For the remaining Staph. aureus strain (M4) gene segments encoding IgG binding domains E, D and A and a new domain BC with a size of 219 bp could be observed. The BC domain appears, with a deletion of a 123 bp segment from the border region between both domains, as fused domain of both previously characterized domains. The Xr-region of this strain had 11 octapeptide repeats.

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Wells, Mark A., Clare Jelinska, Laszlo L. P. Hosszu, C. Jeremy Craven, Anthony R. Clarke, John Collinge, Jonathan P. Waltho, and Graham S. Jackson. "Multiple forms of copper (II) co-ordination occur throughout the disordered N-terminal region of the prion protein at pH 7.4." Biochemical Journal 400, no. 3 (November 28, 2006): 501–10. http://dx.doi.org/10.1042/bj20060721.

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Although the physiological function of the prion protein remains unknown, in vitro experiments suggest that the protein may bind copper (II) ions and play a role in copper transport or homoeostasis in vivo. The unstructured N-terminal region of the prion protein has been shown to bind up to six copper (II) ions, with each of these ions co-ordinated by a single histidine imidazole and nearby backbone amide nitrogen atoms. Individually, these sites have micromolar affinities, which is weaker than would be expected of a true cuproprotein. In the present study, we show that with subsaturating levels of copper, different forms of co-ordination will occur, which have higher affinity. We have investigated the copper-binding properties of two peptides representing the known copper-binding regions of the prion protein: residues 57–91, which contains four tandem repeats of the octapeptide GGGWGQPH, and residues 91–115. Using equilibrium dialysis and spectroscopic methods, we unambiguously demonstrate that the mode of copper co-ordination in both of these peptides depends on the number of copper ions bound and that, at low copper occupancy, copper ions are co-ordinated with sub-micromolar affinity by multiple histidine imidazole groups. At pH 7.4, three different modes of copper co-ordination are accessible within the octapeptide repeats and two within the peptide comprising residues 91–115. The highest affinity copper (II)-binding modes cause self-association of both peptides, suggesting a role for copper (II) in controlling prion protein self-association in vivo.

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Chiesa, Roberto, Pedro Piccardo, Elena Quaglio, Bettina Drisaldi, San Ling Si-Hoe, Masaki Takao, Bernardino Ghetti, and David A. Harris. "Molecular Distinction between Pathogenic and Infectious Properties of the Prion Protein." Journal of Virology 77, no. 13 (July 1, 2003): 7611–22. http://dx.doi.org/10.1128/jvi.77.13.7611-7622.2003.

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ABSTRACT Tg(PG14) mice express a prion protein (PrP) with a nine-octapeptide insertion associated with a human familial prion disease. These animals spontaneously develop a fatal neurodegenerative disorder characterized by ataxia, neuronal apoptosis, and accumulation in the brain of an aggregated and weakly protease-resistant form of mutant PrP (designated PG14spon). Brain homogenates from Tg(PG14) mice fail to transmit disease after intracerebral inoculation into recipient mice, indicating that PG14spon, although pathogenic, is distinct from PrPSc, the infectious form of PrP. In contrast, inoculation of Tg(PG14) mice with exogenous prions of the RML strain induces accumulation of PG14RML, a PrPSc form of the mutant protein that is infectious and highly protease resistant. Like PrPSc, both PG14spon and PG14RML display conformationally masked epitopes in the central and octapeptide repeat regions. However, these two forms differ profoundly in their oligomeric states, with PG14RML aggregates being much larger and more resistant to dissociation. Our analysis provides new molecular insight into an emerging puzzle in prion biology, the discrepancy between the infectious and neurotoxic properties of PrP.

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Huang, Tao, Jian Xu, Jin Xiang, Yajing Lu, Rui Chen, Liqin Huang, Gengfu Xiao, and Guihong Sun. "PrPC interacts with potassium channel tetramerization domain containing 1 (KCTD1) protein through the PrP51-136 region containing octapeptide repeats." Biochemical and Biophysical Research Communications 417, no. 1 (January 2012): 182–86. http://dx.doi.org/10.1016/j.bbrc.2011.11.081.

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Black, G. W., G. P. Hazlewood, G. P. Xue, C. G. Orpin, and H. J. Gilbert. "Xylanase B from Neocallimastix patriciarum contains a non-catalytic 455-residue linker sequence comprised of 57 repeats of an octapeptide." Biochemical Journal 299, no. 2 (April 15, 1994): 381–87. http://dx.doi.org/10.1042/bj2990381.

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A Neocallimastix patriciarum cDNA library was screened for xylanase-expressing clones, which were distinct from the previously characterized N. patriciarum xynA cDNA encoding xylanase A. A single cDNA, designated xynB, which did not exhibit homology with xynA, was isolated. Northern-blot analysis of mRNA from Avicel-grown N. patriciarum showed that xynB hybridized to a 3.4 kb mRNA species. The nucleotide sequence of xynB revealed a single open reading frame of 2580 bp coding for a protein designated xylanase B (XYLB), of M(r) 88,066. The primary structure of XYLB was comprised of a 21-residue N-terminal signal peptide, followed by a 304-amino acid sequence that exhibited substantial homology with the catalytic domains of family F xylanases. The N-terminal domain was linked to a C-terminal 70-residue sequence by a putative linker region, comprising 12 tandem repeats of a sequence containing TLPG as the core sequence, followed by an octapeptide XSKTLPGG where X can be S, K or N, which was repeated in tandem 45 times. Truncated derivatives of xynB encoding the N-terminal 338 residues directed the synthesis of a functional xylanase, confirming that the region of XYLB, which exhibited homology with family F xylanases, constitutes the catalytic domain. To investigate the catalytic properties of XYLB, the catalytic domain was fused to the Escherichia coli maltose-binding protein, and the fusion protein purified by amylose affinity chromatography. The purified enzyme hydrolysed oat, rye and wheat arabinoxylan releasing primarily xylobiose, xylotriose and some xylose. The XYLB fusion did not cleave any cellulosic substrates. The data presented in this report suggest that the multiple xylanases of N. patriciarum arose, not through the duplication of a single gene, but by the transfer of distinct xylanase-encoding DNA sequences into the anaerobic fungus. The possible origin of the xynB gene is discussed.

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Yin, Shaoman, Nancy Pham, Shuiliang Yu, Chaoyang Li, Poki Wong, Binggong Chang, Shin-Chung Kang, et al. "Human prion proteins with pathogenic mutations share common conformational changes resulting in enhanced binding to glycosaminoglycans." Proceedings of the National Academy of Sciences 104, no. 18 (April 24, 2007): 7546–51. http://dx.doi.org/10.1073/pnas.0610827104.

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Mutation in the prion gene PRNP accounts for 10–15% of human prion diseases. However, little is known about the mechanisms by which mutant prion proteins (PrPs) cause disease. Here we investigated the effects of 10 different pathogenic mutations on the conformation and ligand-binding activity of recombinant human PrP (rPrP). We found that mutant rPrPs react more strongly with N terminus-specific antibodies, indicative of a more exposed N terminus. The N terminus of PrP contains a glycosaminoglycan (GAG)-binding motif. Binding of GAG is important in prion disease. Accordingly, all mutant rPrPs bind more GAG, and GAG promotes the aggregation of mutant rPrPs more efficiently than wild-type recombinant normal cellular PrP (rPrPC). Furthermore, point mutations in PRNP also cause conformational changes in the region between residues 109 and 136, resulting in the exposure of a second, normally buried, GAG-binding motif. Importantly, brain-derived PrP from transgenic mice, which express a pathogenic mutant with nine extra octapeptide repeats, also binds more strongly to GAG than wild-type PrPC. Thus, several rPrPs with distinct pathogenic mutations have common conformational changes, which enhance binding to GAG. These changes may contribute to the pathogenesis of inherited prion diseases.

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Jones, David T., Ryan A. Townley, Jonathan Graff-Radford, Hugo Botha, David S. Knopman, Ronald C. Petersen, Clifford R. Jack, Val J. Lowe, and Bradley F. Boeve. "Amyloid- and tau-PET imaging in a familial prion kindred." Neurology Genetics 4, no. 6 (December 2018): e290. http://dx.doi.org/10.1212/nxg.0000000000000290.

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ObjectiveTo study the in vivo binding properties of 18F-AV-1451 (tau-PET) and Pittsburgh compound B (PiB-PET) in a unique kindred with a familial prion disorder known to produce amyloid plaques composed of prion protein alongside Alzheimer disease (AD)–like tau tangles.MethodsA case series of 4 symptomatic family members with the 12-octapeptide repeat insertion in the PRNP gene were imaged with 3T MRI, PiB-PET, and tau-PET in their fourth decade of life.ResultsThere was significant neocortical uptake of the tau-PET tracer in all 4 familial prion cases. However, PiB-PET images did not demonstrate abnormally elevated signal in neocortical or cerebellar regions for any of the patients.ConclusionsIn vivo detection of molecular hallmarks of neurodegenerative diseases will be a prerequisite to well-conducted therapeutic trials. Understanding the in vivo behavior of these PET biomarkers in the setting of various neurodegenerative processes is imperative to their proper use in such trials and for research studies focused on the basic neurobiology of neurodegeneration. This study supports the high specificity of neocortical 18F-AV-1451 binding to AD-like tau and the lack of PiB binding to PrP plaques. It is uncertain how early in the disease course tau pathology appears in the brains of individuals who carry this PRNP gene mutation or how it evolves throughout the disease course, but future longitudinal 18F-AV-1451 imaging of symptomatic and asymptomatic individuals in this kindred will help address these uncertainties.

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Martin, D. R., A. Yuryev, K. R. Kalli, D. T. Fearon, and J. M. Ahearn. "Determination of the structural basis for selective binding of Epstein-Barr virus to human complement receptor type 2." Journal of Experimental Medicine 174, no. 6 (December 1, 1991): 1299–311. http://dx.doi.org/10.1084/jem.174.6.1299.

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Epstein-Barr virus (EBV) is an oncogenic herpesvirus that selectively infects and immortalizes human B lymphocytes. One determinant of this narrow tropism is human CR2, the only viral receptor within the superfamily of proteins that contain short consensus repeats (SCRs). Human CR2 serves as a receptor for both C3dg and the gp350/220 glycoprotein of EBV, and binds the monoclonal antibody (mAb) OKB7, which blocks binding of both ligands to the receptor. In contrast, although murine CR2 is capable of binding human C3dg and this interaction can be blocked with the mAb 7G6, it does not bind OKB7 or EBV. We have determined the structural basis for absolute specificity of EBV for human CR2 through characterization of a panel of 24 human-murine chimeric receptors, all of which bind human C3dg. The results indicate that preferential binding of EBV to human CR2 is not due to unique amino acids that are capable of binding the virus, but reflects a distinct receptor conformation that can be achieved in murine CR2 with single amino acid substitutions in two discontinuous regions of the primary structure: replacement of proline at position 15 with the corresponding serine from human CR2, and elimination of a potential N-linked glycosylation site between SCR-1 and SCR-2. Furthermore, species-specific binding of EBV, OKB7, and 7G6 can all be manipulated through substitutions among residues 8-15, suggesting that this octapeptide is part of a structural determinant that is critical for binding of both viral and natural ligands to CR2.

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Okabe, Reiko, Kiyoshi Nakatsuka, Masaaki Inaba, Takami Miki, Hiroshi Naka, Hideki Masaki, Atushi Moriguchi та Yoshiki Nishizawa. "Clinical Evaluation of the Elecsys β-CrossLaps Serum Assay, a New Assay for Degradation Products of Type I Collagen C-Telopeptides". Clinical Chemistry 47, № 8 (1 серпня 2001): 1410–14. http://dx.doi.org/10.1093/clinchem/47.8.1410.

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Abstract Background: The Elecsys β-CrossLaps serum assay measures type I collagen degradation fragments (β-CTx) that contain the β-isomerized octapeptide EKAHD-β-GGR. We investigated the analytical performance of the assay and changes in β-CrossLaps in patients with metabolic bone diseases. Methods: The electrochemiluminescent sandwich immunoassay uses two monoclonal antibodies directed against different regions of the linear EKAHD-β-GGR. Results: β-CrossLaps (β-CTx) immunoreactivity was stable in serum and plasma stored at 4 °C for 24 h or at room temperature for 4 h, and it did not decrease appreciably in samples stored at −30 °C for 12 weeks. Nine cycles of repeated freezing-thawing did not affect serum β-CTx. The intra- and interassay imprecision (CVs) for four samples was ≤2.6% (n = 10) and ≤4.1% (n = 10), respectively. The mean day-to-day biological variation (CV) was 20% in 10 postmenopausal women (n = 10 days). Serum β-CTx and osteocalcin were correlated in patients with hyperparathyroidism (r = 0.796; P <0.0001; n = 28), chronic renal failure on hemodialysis (r = 0.784; P = 0.0003; n = 16), hypoparathyroidism (r = 0.950; P = 0.0001; n = 11), and pseudohypoparathyroidism (r = 0.987; P = 0.130; n = 4). Serum β-CTx decreased by 47.4% ± 8.8% (mean ± SD) and 60.7% ± 6.5% at 3 and 6 months, respectively, after initiation of estrogen replacement therapy in 34 women. These decreases were greater than the decreases in urinary excretion of deoxypyridinoline (31.8% ± 3.9% and 38.1% ± 4.4%, respectively) or pyridinoline cross-linked C-terminal telopeptide of type I collagen (15.9% ± 3.9% and 16.9% ± 4.6%, respectively). Conclusions: The Elecsys β-CrossLaps serum assay provides a potentially useful tool for assessing bone resorption state, including its response to estrogen replacement therapy.

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Hara, Hideyuki, Hironori Miyata, Nandita Rani Das, Junji Chida, Tatenobu Yoshimochi, Keiji Uchiyama, Hitomi Watanabe, Gen Kondoh, Takashi Yokoyama, and Suehiro Sakaguchi. "Prion Protein Devoid of the Octapeptide Repeat Region Delays Bovine Spongiform Encephalopathy Pathogenesis in Mice." Journal of Virology 92, no. 1 (October 18, 2017). http://dx.doi.org/10.1128/jvi.01368-17.

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ABSTRACTConformational conversion of the cellular isoform of prion protein, PrPC, into the abnormally folded, amyloidogenic isoform, PrPSc, is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals. We previously reported that the octapeptide repeat (OR) region could be dispensable for converting PrPCinto PrPScafter infection with RML prions. We demonstrated that mice transgenically expressing mouse PrP with deletion of the OR region on the PrP knockout background, designated Tg(PrPΔOR)/Prnp0/0mice, did not show reduced susceptibility to RML scrapie prions, with abundant accumulation of PrPScΔOR in their brains. We show here that Tg(PrPΔOR)/Prnp0/0mice were highly resistant to BSE prions, developing the disease with markedly elongated incubation times after infection with BSE prions. The conversion of PrPΔOR into PrPScΔOR was markedly delayed in their brains. These results suggest that the OR region may have a crucial role in the conversion of PrPCinto PrPScafter infection with BSE prions. However, Tg(PrPΔOR)/Prnp0/0mice remained susceptible to RML and 22L scrapie prions, developing the disease without elongated incubation times after infection with RML and 22L prions. PrPScΔOR accumulated only slightly less in the brains of RML- or 22L-infected Tg(PrPΔOR)/Prnp0/0mice than PrPScin control wild-type mice. Taken together, these results indicate that the OR region of PrPCcould play a differential role in the pathogenesis of BSE prions and RML or 22L scrapie prions.IMPORTANCEStructure-function relationship studies of PrPCconformational conversion into PrPScare worthwhile to understand the mechanism of the conversion of PrPCinto PrPSc. We show here that, by inoculating Tg(PrPΔOR)/Prnp0/0mice with the three different strains of RML, 22L, and BSE prions, the OR region could play a differential role in the conversion of PrPCinto PrPScafter infection with RML or 22L scrapie prions and BSE prions. PrPΔOR was efficiently converted into PrPScΔOR after infection with RML and 22L prions. However, the conversion of PrPΔOR into PrPScΔOR was markedly delayed after infection with BSE prions. Further investigation into the role of the OR region in the conversion of PrPCinto PrPScafter infection with BSE prions might be helpful for understanding the pathogenesis of BSE prions.

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Kroll, François, Athanasios Dimitriadis, Tracy Campbell, Lee Darwent, John Collinge, Simon Mead, and Emmanuelle Vire. "Prion protein gene mutation detection using long-read Nanopore sequencing." Scientific Reports 12, no. 1 (May 18, 2022). http://dx.doi.org/10.1038/s41598-022-12130-7.

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AbstractPrion diseases are fatal neurodegenerative conditions that affect humans and animals. Rapid and accurate sequencing of the prion gene PRNP is paramount to human prion disease diagnosis and for animal surveillance programmes. Current methods for PRNP genotyping involve sequencing of small fragments within the protein-coding region. The contribution of variants in the non-coding regions of PRNP including large structural changes is poorly understood. Here, we used long-range PCR and Nanopore sequencing to sequence the full length of PRNP, including its regulatory region, in 25 samples from blood and brain of individuals with inherited or sporadic prion diseases. Nanopore sequencing detected the same variants as identified by Sanger sequencing, including repeat expansions/deletions. Nanopore identified additional single-nucleotide variants in the non-coding regions of PRNP, but no novel structural variants were discovered. Finally, we explored somatic mosaicism of PRNP’s octapeptide repeat region, which is a hypothetical cause of sporadic prion disease. While we found changes consistent with somatic mutations, we demonstrate that they may have been generated by the PCR. Our study illustrates the accuracy of Nanopore sequencing for rapid and field prion disease diagnosis and highlights the need for single-molecule sequencing methods for the detection of somatic mutations.

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Võ, Tuấn Cường, Hương Giang Lê, Jung-Mi Kang, Mya Moe, Haung Naw, Moe Kyaw Myint, Jinyoung Lee, Woon-Mok Sohn, Tong-Soo Kim, and Byoung-Kuk Na. "Genetic polymorphism and natural selection of circumsporozoite protein in Myanmar Plasmodium vivax." Malaria Journal 19, no. 1 (September 4, 2020). http://dx.doi.org/10.1186/s12936-020-03366-7.

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Abstract Background Circumsporozoite surface protein (CSP) of malaria parasites has been recognized as one of the leading vaccine candidates. Clinical trials of vaccines for vivax malaria incorporating Plasmodium vivax CSP (PvCSP) have demonstrated their effectiveness in preventing malaria, at least in part. However, genetic diversity of pvcsp in the natural population remains a major concern. Methods A total of 171 blood samples collected from patients infected with Plasmodium vivax in Myanmar were analysed in this study. The pvcsp was amplified by polymerase chain reaction, followed by cloning and sequencing. Polymorphic characteristics and natural selection of pvcsp population in Myanmar were analysed using DNASTAR, MEGA6 and DnaSP programs. The polymorphic pattern and natural selection of publicly accessible global pvcsp sequences were also comparatively analysed. Results Myanmar pvcsp sequences were divided into two subtypes VK210 and VK247 comprising 143 and 28 sequences, respectively. The VK210 subtypes showed higher levels of genetic diversity and polymorphism than the VK247 subtypes. The N-terminal non-repeat region of pvcsp displayed limited genetic variations in the global population. Different patterns of octapeptide insertion (ANKKAEDA in VK210 and ANKKAGDA in VK247) and tetrapeptide repeat motif (GGNA) were identified in the C-terminal region of global pvcsp population. Meanwhile, the central repeat region (CRR) of Myanmar and global pvcsp, both in VK210 and VK247 variants, was highly polymorphic. The high level of genetic diversity in the CRR has been attributed to the different numbers, types and combinations of peptide repeat motifs (PRMs). Interestingly, 27 and 5 novel PRMs were found in Myanmar VK210 and VK247 variants, respectively. Conclusion Comparative analysis of the global pvcsp population suggests a complex genetic profile of pvcsp in the global population. These results widen understanding of the genetic make-up of pvcsp in the global P. vivax population and provide valuable information for the development of a vaccine based on PvCSP.

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Putaporntip, Chaturong, Napaporn Kuamsab, Rattanaporn Rojrung, Sunee Seethamchai, and Somchai Jongwutiwes. "Structural organization and sequence diversity of the complete nucleotide sequence encoding the Plasmodium malariae merozoite surface protein-1." Scientific Reports 12, no. 1 (September 16, 2022). http://dx.doi.org/10.1038/s41598-022-19049-z.

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AbstractThe merozoite surface protein-1 (MSP1) is a prime candidate for an asexual blood stage vaccine against malaria. However, polymorphism in this antigen could compromise the vaccine’s efficacy. Although the extent of sequence variation in MSP1 has been analyzed from various Plasmodium species, little is known about structural organization and diversity of this locus in Plasmodium malariae (PmMSP1). Herein, we have shown that PmMSP1 contained five conserved and four variable blocks based on analysis of the complete coding sequences. Variable blocks were characterized by short insertion and deletion variants (block II), polymorphic nonrepeat sequences (block IV), complex repeat structure with size variation (block VI) and degenerate octapeptide repeats (block VIII). Like other malarial MSP1s, evidences of intragenic recombination have been found in PmMSP1. The rate of nonsynonymous nucleotide substitutions significantly exceeded that of synonymous nucleotide substitutions in block IV, suggesting positive selection in this region. Codon-based analysis of deviation from neutrality has identified a codon under purifying selection located in close proximity to the homologous region of the 38 kDa/42 kDa cleavage site of P. falciparum MSP1. A number of predicted linear B-cell epitopes were identified across both conserved and variable blocks of the protein. However, polymorphism in repeat-containing blocks resulted in alteration of the predicted linear B-cell epitope scores across variants. Although a number of predicted HLA-class II-binding peptides were identified in PmMSP1, all variants of block IV seemed not to be recognized by common HLA-class II alleles among Thai population, suggesting that diversity in this positive selection region could probably affect host immune recognition. The data on structural diversity in PmMSP1 could be useful for further studies such as vaccine development and strain characterization of this neglected malaria parasite.

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Scalabrino, Giuseppe, and Daniela Veber. "VITAMIN B12 AND NORMAL PRIONS: TWO FIELDS APPARENTLY SO FAR, BUT IN REALITY SO NEAR." Istituto Lombardo - Accademia di Scienze e Lettere - Rendiconti di Scienze, December 30, 2014. http://dx.doi.org/10.4081/scie.2014.192.

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Cobalamin (Cbl) deficiency causes an imbalance in some cytokines and growth factors in the central nervous system and peripheral nervous system of the rat, and in the serum and cerebrospinal fluid (CSF) of adult Cbl-deficient (Cbl-D) patients. We hypothesized that an imbalance in normal prion (PrPC) levels and/or synthesis might be involved in the pathogenesis of Cbl-D neuropathy. Using different appropriate enzyme-linked immunosorbent assays (ELISAs), we determined the levels of Cbl, tumour necrosis factor-a, epidermal growth factor, and PrPC in spinal cord (SC) and CSF of Cbl-D rats treated or not with different molecules; in serum, CSF from Cbl-D or multiple sclerosis (MS) patients; and in post-mortem SC samples taken from MS patients and control patients. We have demonstrated that: (i) Cbl deficiency induces excess PrPC regions (particularly octapeptide repeated (OR) region) in rat SC; (ii) the SC increase is mediated by a local Cbl deficiency-induced excess of tumour necrosis factor- a; and (iii) CSF and serum PrPC concentrations in Cbl-D patients are significantly higher than in controls. CSF PrPC concentrations are significantly lower in MS patients than neurological controls. The Cbl, EGF, and PrPC levels were significantly decreased in post-mortem MS SCs in comparison with controls

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Kim, So Young, Fuming Zhang, David A. Harris, and Robert J. Linhardt. "Structural Features of Heparin and Its Interactions With Cellular Prion Protein Measured by Surface Plasmon Resonance." Frontiers in Molecular Biosciences 7 (November 26, 2020). http://dx.doi.org/10.3389/fmolb.2020.594497.

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Self-propagating form of the prion protein (PrPSc) causes many neurodegenerative diseases, such as Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Scheinker syndrome (GSS). Heparin is a highly sulfated linear glycosaminoglycan (GAG) and is composed of alternating D-glucosamine and L-iduronic acid or D-glucuronic acid sugar residues. The interactions of heparin with various proteins in a domain-specific or charged-dependent manner provide key roles on many physiological and pathological processes. While GAG-PrP interactions had been previously reported, the specific glycan structures that facilitate interactions with different regions of PrP and their binding kinetics have not been systematically investigated. In this study, we performed direct binding surface plasmon resonance (SPR) assay to characterize the kinetics of heparin binding to four recombinant murine PrP constructs including full length (M23–230), a deletion mutant lacking the four histidine-containing octapeptide repeats (M23–230 Δ59–90), the isolated N-terminal domain (M23–109), and the isolated C-terminal domain (M90–230). Additionally, we found the specific structural determinants required for GAG binding to the four PrP constructs with chemically defined derivatives of heparin and other GAGs by an SPR competition assay. Our findings may be instrumental in developing designer GAGs for specific targets within the PrP to fine-tune biological and pathophysiological activities of PrP.

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