Disease relevance of PRM1

• Sperm protamine deficiency has been associated with human male infertility [1].
• Changes in the expression of P1 and P2 protamines have been found to be associated with infertility in man [2].
• For this reason, despite its known limitations and toxicities, heparin use remains high because it is the only anticoagulant that can be controlled by an antidote, the polypeptide protamine [3].
• Residues 150-183 are known to form a protamine-like domain required for packaging RNA, and residues 1-149 form the 'assembly domain' that polymerizes into capsids and, unusually for a capsid protein, is highly alpha-helical [4].
• We now report the successful, cell-free isolation of an unusual, filterable agent prepared in protamine sulphate buffer from primary and animal-passaged lymphomas, which produces lymphomas with good efficiency when injected subcutaneously (s.c.) into newborn Syrian inbred (LSH) and random-bred (LVG) hamster [5].

Psychiatry related information on PRM1

• Traditional regimens of empiric heparin dosing and a fixed-dose ratio of protamine to heparin for reversal of anticoagulation do not account for individual differences in the half-life of heparin, clearance of heparin, and duration of CPB, particularly in children [6].
• Furthermore, the amphetamine resistance appears to be the result of the diabetic state, since amphetamine-induced stereotyped behavior could be reinstated in alloxan-injected rats by the administration of protamine zinc insulin for ten days [7].
• There were no differences between the two groups in terms of anesthetic drug usage, total heparin or protamine doses, blood loss, transfusion requirements, or duration of ICU stay.(ABSTRACT TRUNCATED AT 250 WORDS)[8]
• Initial heparin and subsequent protamine doses were determined by constructing a heparin-activated coagulation time response curve [9].

High impact information on PRM1

• Haploinsufficiency of protamine-1 or -2 causes infertility in mice [10].
• Life-threatening reactions to intravenous protamine, administered to reverse heparin anticoagulation, have been reported with increasing frequency as a consequence of the escalating use of cardiac catheterization and coronary bypass surgery [11].
• Functional coagulation studies revealed that the purified inhibitor had cofactor activity with antithrombin III that could be abolished by prior incubation with protamine sulfate or platelet factor 4 [12].
• Single subcutaneous injections of 50 microng of protamine zinc somatostatin raised preprandial blood glucose levels to 83+/-3 mg per deciliter for four to five days although preprandial hormone levels were unchanged [13].
• At the early protamine stage of testis development, polysomal and postribosomal supernatant fractions contain almost equal quantities of poly(A)+ protamine mRNA, but poly(A)- protamine mRNA was found almost entirely in the polysomes [14].

Chemical compound and disease context of PRM1

• Upon infusion of the positively charged protein, protamine sulfate, the reverse was observed with mPF4(+/-) and mPF4(-/-) animals having improved thrombosis, with the hPF4(+) animals having worsened thrombus formation [15].
• Here we demonstrate with magnetic resonance imaging (MRI) that an intravenous dose of protamine labeled with gadolinium accumulated within the parenchyma of subcutaneous implants of a mammary adenocarcinoma in Fischer 344 rats [16].
• It has been shown that, in streptozotocin diabetic rats, protamine-retarded insulin administered in vivo stimulates intimal hyperplasia in balloon-injured carotid artery [17].
• CONCLUSION: Increased bradykinin contributes to protamine-related hypotension through its B(2) receptor in ACE inhibitor-treated patients [18].
• A recombinant bifunctional fusion protein, which consists of a human antibody Fab targeting moiety [directed against gp120, the envelope glycoprotein of human immunodeficiency virus (HIV)-1] and a human DNA binding moiety (protamine), is used as a gene carrier [19].

Biological context of PRM1

• The spermatid-specific nucleoprotamine genes PRM1 and PRM2 and the transition protein gene TNP2 are clustered at a single site on human chromosome 16p13 [20].
• The spermatids of men with severely deranged spermatogenesis exhibited significant lower PRM1 mRNA expression than in the other patient groups [21].
• These results emphasize the role of PRM1 as a potentially critical factor in post-ICSI embryonic development [21].
• We also observed one SNP in the 3' non-coding region of the PRM1 gene, and two SNPs within the intron of the PRM2 gene [22].
• In mouse and human, the genes encoding protamines PRM1, PRM2 and transition protein TNP2 are found clustered together on chromosome 16 [23].

Anatomical context of PRM1

• Analysis of the haploid-expressed human PRM1 --> PRM2 --> TNP2 genic domain has revealed two regions of attachment to the sperm nuclear matrix [24].
• Spermatid PRM1 expression was lower in non-pregnant couples than in pregnant couples [21].
• The cellular expression of PRM1 and PRM2 mRNAs in single testicular spermatids from 41 azoospermic patients (in whom testicular spermatozoa were subsequently recovered and submitted for TESE-ICSI) was determined by radioactive in situ hybridization [21].
• Coordinate expression of the PRM1, PRM2, and TNP2 multigene locus in human testis [25].
• CONCLUSION(S): In the present patient the breakpoint at 16p13.3 could have disrupted or harbored the PRM1, PRM2, or TNP2 genes responsible for the replacement of the histones involved in packaging the DNA into the sperm head [26].

Associations of PRM1 with chemical compounds

• Previously, we have shown that the human PRM1 --> PRM2 --> TNP2 locus exists as a single chromatin domain bounded by two male germ cell-specific MARs, i.e. Matrix Attachment Regions [23].
• The relative proportions of protamine 1, 2, and 3 were determined by scanning microdensitometry following electrophoresis of total protamine in polyacrylamide gels [27].
• Human protamine P1 is highly homologous with the protamines isolated from bull, boar, ram and mouse sperm cells, but human protamine P2 shows a novel type of structure, although also here the dominant amino acids are arginine and cysteine [28].
• The amino-acid sequence of protamine P1 was determined by analysing the intact protein and the fragments obtained by cyanogen bromide cleavage [28].
• Purified MBP was studied for capacity to regulate the generation of classical and alternative-amplification pathway C3 convertases because previous studies have shown that other polycations (protamine, poly-L-lysine) and polyanions (heparin) may play important roles in regulating C activation [29].

Physical interactions of PRM1

• Heparin-protamine complex was less stimulant to expression of CD11b and L-selectin than heparin or protamine (P < 0.05) [30].
• Although BDNF was not transported through the BBB in vivo, this cationic peptide was avidly bound by isolated human brain capillaries via a low-affinity, high-capacity system that was inhibited by protamine and by serum protein binding of BDNF [31].
• The driving force for arginine-rich selection appears to be the DNA-binding function of protamine P1 and an interaction with a protein kinase in the fertilized egg [32].

Enzymatic interactions of PRM1

• In addition, the kinase phosphorylates peptide epsilon and myelin basic protein with equal efficiency but phosphorylates Kemptide and protamine sulfate poorly [33].
• Insulin-stimulated protamine kinase (cPK) and protein kinase C (PKC) phosphorylated eukaryotic protein synthesis initiation factor 4E (eIF-4E) on serine and threonine residues located on an identical tryptic fragment as judged by two-dimensional phosphopeptide mapping [34].

Regulatory relationships of PRM1

• These results are in agreement with the probable role of TRBP in the control of human protamine mRNA translation [35].
• Protamine significantly inhibited factor VII (FVII) activation but not the dissected FX activation [36].
• Binding of 125I-labeled PF4 was partially inhibited by the presence of increasing concentrations of protamine sulfate and basic fibroblast growth factor [37].
• CONCLUSIONS: Protamine enhanced fibrinolysis by decreasing clot strength by diminishing TF-initiated thrombin generation [38].
• Antibodies to bFGF, as well as suramin and protamine sulfate also suppress the basal levels of plasminogen activator and DNA synthesis in bovine aortic endothelial cells [39].

Other interactions of PRM1

• Thus, the MARs bounding the PRM1 --> PRM2 --> TNP2 protamine domain have many and varied functions [40].
• The genes for three of these low molecular weight basic nuclear proteins exist as a single linear array of PRM1, PRM2, and TNP2 on human chromosome 16p13 [41].
• Analysis described here supports the view that a fourth candidate coding region, gene4/Prm3, was derived from PRM1 during the genesis of the PRM1-->PRM2-->TNP2 domain [42].
• Electron microscopic in situ hybridization study of simultaneous expression of TNP1 and PRM1 genes in human spermatids [43].
• The present study reports that androgen receptor occupation by CPA preferentially reduces the levels of spermatidal protamine in testis and spermatozoa involved in nuclear chromatin condensation [44].

Analytical, diagnostic and therapeutic context of PRM1

• Chromosomal localization of the human protamine genes, PRM1 and PRM2, to 16p13.3 by in situ hybridization [45].
• Immunoblotting experiments (using H2B, PRM1, and PRM2 antibodies) were conducted to confirm the specificity of the bands [46].
• Protamines are low molecular weight, highly basic nuclear proteins involved in the condensation of sperm chromatin. cDNA clones for human protamine 1 and 2 (PRM1 and PRM2) were used for Northern blot experiments with RNA from different human tissues [47].
• Sequence analysis of the conserved protamine gene cluster shows that it contains a fourth expressed gene [48].
• Semi-quantitative real-time RT-PCR was used to quantify P1 and P2 mRNA levels [1].

References