The function of human body is determined by various factors that play key role in contributing to physiological or homeostatic pathway regulation. This in turn relies on the vitality of the body fluids like serum or plasma as there are inherent essential components being present like proteins, coagulating factors, hormones minerals and ionic substances etc. The central role is complex and interrelated with structural characteristic features. Understanding the positional importance, significance of associations and their over all functions is of paramount significance for the present day investigations.
An aberration or defect in the normal role of the essential compounds of body fluids may be problematic clinical aspect. Depending on the type of disorder or condition, the bodily demands of the proteins or other substances may be under tight control. From the molecular level, regulations would be put on operation. As such, there is a need to explore the available literature to gain insightful information. In the recent period, much research attention was given to plasma proteins due to their clinical significance. The present description is based on Histidine linked proteins known as Histidine Rich Glycoprotein (HRG).
This protein is found in the plasma of vertebrates and known for its involvement in the control of several hematological processes like immune complex production and its regulation, clearance, adherence to lymphocytes and proliferation ,control of Blood clotting and fibrinolysis and the transport of metal cations like Zn2+, (Hulett and Parish, 2000). HRG is involved in blood coagulation events be becoming a substrate for plasma factor XIIIa as observed in animal studies (Halkier 1994).The function of HRG is of central research interest due to its association with ligands(Hulett and Parish, 2000).
These could be T-cells, platelets, immunoglobulin G (IgG), membrane attack complex and complement components C1q, blood coagulating molecules, like heparin, thrombospondin, plasminoigen, and fibrinogen (Hulett and Parish, 2000). Thus HRGP involvesin cell mediated immunoreguatory functions by binding with T- lymphocytes (Saigo et al., 1989).
This was revealed when a study was undertaken to assess the interacting mechanisms of HRG with the complement using techniques like optical biosensor and ELISA (Gorgani et al., 1997). HRG is reported to possess 81 kDa (native) and the 30 kDa proteins (presumably proteolytic N-terminal fragments of HRG) to attach with the C1q (Gorgani et al., 1997). This was revealed when gene mapping of HRG was performed and intron Hregion of HRG was found missing (Hennis et al., 1994). These interactions occur in Zn2+-modulated manner and could influence the synthesize of immune complexes (Gorgani et al., 1997). In detail, HRG enables binding of IgG to necrotic cells and helps in the phagocytosis of necrotic cells which is dependant on Fc gamma RI-dependent pathway (Poon, Parish & Hulett 2010).
This occurs in a well cooperated manner with the aid of Heparin sulfate (HS) present on the cell surface of monocytic cell line THP-1(Poon, Parish & Hulett 2010).Heparin, considered as HRG ligand helps in the regulation of this process (Poon, Parish & Hulett 2010). HRG plays vital role in influencing the plasminogen/plasmin system which is essential for tumour metastasis, angiogenesis, and tissue remodeling (Poon et al., 2009). Plasmin produced from the plasminogen cleaves HRG into fragments which improve the attachment of plasminogen to heparin-coated surfaces (Poon et al., 2009). Peterson, Morgan and Blackburn (1987) propounded that HRG induced inhibition is dependant on pH indicating the association between HRG and Heparin.
Lijnen, Holylaerts and Collen (1983) described that HRGP neutralizes heapirn in plasma further indicating its adhesion with the molecule in anticoagulation.HRG contributes to low heparin proportion when it is nor present in plasma thus leading to high heparin influence on on thrombin inhibition by stimulated protein C prevention with protein C inhibitor and antithrombin (Kazama et al., 1992).
HRG has negligible role in in the fibrinolytic system, due to abnormal proportion of HRG has no role in the plasminogen activation (Angles-Cano et al., 1993).A case study revealed that the absence of HRG leads to cerebral sinus thrombosis indicating its vital role in the antithrombosis (Shigekiyo et al.,1993). Similarly, another family with defect in HRG was discovered where pulmonary embolism was observed in two patients aged 36 and 59, thus indicating antithrombotic role of HRGP to minimize thrombotic aberrations (Souto et al., 1996).
Ann-Maree et al.(2004) revealed that recombinant proteins when expressed with ubiquitin on fusing could enhance early characterization of peptides and proteins. Therefore, the process of HRG proteolytic cleavage by the action of plasmin is a essential HRG mediated function for plasminogen/plasmin system (Poon et al., 2009). HRG is central for the innate immune system. It associates with concanavalin A (Con A), and facilitates changes in the external appearance and attachment of human leukemic T-cell line MOLT-4 to culture plates(Ohta et al., 2009).
The cell surface of Fc gamma receptors or glycosaminoglycan had no role to play in the cellular event (Ohta et al., 2009). These processes occur through the functions of ATP synthase which serves as binding protein for HRG (Ohta et al., 2009). Hence, HRG induces morphological variations in cells essential for the immune system (Ohta et al., 2009). The structure of HRG is complex. It occurs as single chain molecule with molecular weight 67,000(Heimburger, et al., 1972).
The histidine-rich region of HRG is similar to that of kininogen, a high molecular weight modulator in association with blood coagulation activation system (Koide et al., 1986). It consists of 507 motifs of amino acid residues which are present in the blood circulation at increased doses (Koide et al., 1986). Especially, it has good residues of proline and histidine in the carboxy-terminal region (Koide et al., 1986). HRG gene is found on chromosome 3q28-q29 and has 11 kb with seven exons and six introns (Koide, 1988).
Its structure is similar to family of cystatin like cystatin SN, SA, and C and high–molecular weight kininogen. The histidine-rich region of HRG is homologous to the corresponding area of high molecular weight kininogen, a modulator in the contact activation system of blood coagulation (Koide, 1988). Earlier Silverstein et al. (1985) informed that HRGP forms complex with Thrombospondin (TSP) and plasminogen (Plg) as TSP-HRGP-Plg organization is central for proteolytic and prothrombotic functions (Silverstein et al.1985). The structure of HRG consists 2067 nucleotides as revealed by sequencing experiments conducted on 3 overlapping cDNA clones (Takehiko Koide, 1986).
These consisted of 352 nucleotides of 3′-noncoding sequence and a poly(A) tail of 16 nucleotides, a stop codon of TAA, 1521 nucleotides that code the mature protein of 507 amino acids, 54 nucleotides coding for a leader sequence of 18 amino acids, and 121 nucleotides of 5′-noncoding sequence( Koide,1986). This is consistent with the earlier description that indicated that HRG has multidomain structure with histidine-rich region and two cystatin-like regions at the N-terminus.near the C-ter minus, These regions are hanged by proline-rich regions (PRR). Koide and Odani, 1987).HRP exerts angiogenic effect that relies on its histidine/proline-rich domain(Dixelius, et al., 2006).
To this end,a 35-amino-acid peptide, HRGP330, was detected whose function is arrest in endothelial cell motility, inhibition of vascular endothelial growth factor (VEGF)-induced tyrosine phosphorylation of the FAK substrate alpha-actinin, focal adhesion kinase (FAK) functions, focal adhesion function by disruption of integrin-linked kinase (ILK) (Dixelius, et al., 2006). HRG is very important because its activity is associated with various important biological functions. Various studies have been carried out to determine its significance. It plays key role as an inhibitor of fibrinolysis This process is essential for minimizing the complex synthesis with plasminogen in circulation (Leebeek et al., 1989).
In conditions like liver cirrhosis (Child A), HRG levels show an increase(Leebeek et al., 1989).This indicates that increased HRG levels in this condition may yield significant information on familial thrombosis (Leebeek et al., 1989). This was strengthened by another report. Corrigan and Jeter (1990) have described that HRG levels in newborns are very low which could be due to their altered lytic system. This was revealed when the plasma levels of HRG were measured in the cord blood (Corrigan and Jeter, 1990). The HRG levels were low in premature newborns compared to their term newborns and also adults (Corrigan and Jeter, 1990).
This could indicate that there is requirement of plasminogen to facilitate enough fibrin binding (Corrigan and Jeter, 1990). HRG is important as the relationship between its multidomain structure and many ligands is central in understanding various biological systems(Blank and Shoenfeld, 2008). The noted HRG ligands are FcgR, and complement, fibrinogen, IgG, thrombospondin, plasminogen, heparan sulphate, Zn2+, tropomyosin and heparin (Blank and Shoenfeld, 2008). The multi-domain property of HRG and varied ligand binding features reflect its action as an extracellular adaptor protein that connects various ligands together on surfaces of several cells (Blank and Shoenfeld, 2008). HRG could improve the removal of necrotic and apoptotic phagocytes and also immune complexes (Blank and Shoenfeld, 2008).
Thus, HRG induces phagocytosis in vivo by identifying necrotic cells and leading to their exit (Jones, et al.2005). Next, there is a further need to now about the role of HRG in antiangiogenic and antitumor activities. This functional activity of HRG is due to its histidine-proline-rich (H/P) domain and is facilitated through the attachment to cell-surface tropomyosin which is present in endothelial cells that are stimulated by fibroblast growth factor-2(Donate et al., 2004). This was revealed when HRG was characterized through the association of H/P domain with tropomyosin (Donate et al., 2004).
By employing the technique of tropomyosin binding assay, the interaction between the synthetic peptide HHPHG with the tropomyosin and the subsequent inhibition of angiogenesis and tumor growth were studied (Donate et al., 2004)
This was further strengthened by another report. The action of systemic HRGP/HRGP330 on vascular system has implications as far as the inhibition of angiogenesis is concerned as HRGP belongs to cystatin family. Fetuin – B and kininogen exert antiangiogenic action through histidine-rich domain. These key factors when removed from the chromosome 16 could lead to ‘‘angiogenic switch’’ in a transgenic model developed to study multistage tumorigenesis (Dixilieus et al., 2006).
HRGP participates in signal transduction to enable the organization of endothelial cells as vessel motiffs which occrs through the disorganization of cytoskeleton (Chunsik et al., 2006). A study indicated that HRG genetics plays important role in the generation of plasma HGR levels (Hennis etal., 1995). Novel di-allelic polymorphism in HRG was found in families in a codominant inheritance pattern (Hennis etal., 1995).
There was significant heritability, with age effect and better influence of environmental factors (Hennis etal., 1995). Hence, the inheritance pattern of HRG levels may help us to identify the genetically susceptible individuals to various HRG related disorders or clinical conditions. The antiangiogenic effect of HRG could be pointed toward the disorganization of be due to disruption of focal adhesion outcome followed by minimized transfer migration and attachment of endothelial cells (Vanwildemeersch et al., 2006).
For example, HRG disrupts the formation of grade IV tumors by preventing the occurrence of malignant glioma. This was revealed when a mouse model RCAS/TV-A with brain tumors were stimulated with platelet-derived growth factor-B (PDGF-B (Maria Karrlander et al., 2009).
Guan et al (2004) further strengthened that proline rich HRGP prevents angiogenesis by attaching with tropomyosin cell surface. Juarez et al. (2002) described that a domain named as rbHPRG involves in lessening the tumor cell population through the H/P domain when the cell lines of tumor were stimulated in Matrigel plug assay. Animal studies have demonstrated that HRG with its antiangiogenic domain actively contributes to the efficient control of hemostasis and angiogenesis (Asa Thulin et al., 2010).
HRG prevents the angiogenesis prompted by heparin-dependent basic fibroblast growth factor (bFGF) indicating its involvement in tumor angiogenesis’ (Hidenori et al., 2009). Christopher etal. (1999) have shown that phosphomannopentaose, PI-88, an antitumor drug is a reliable drug candidate for treating cancers. Maria (2009) described that HRG has low influence on the tumor occurrence rate.However, it could disrupt the glioblastoma development.
Thus, it may indicate that HRG is important for cancer detection.Due to its multi ligand structure, HRG could be exploited as a potential tool for tumor detection. Its involvement in the inhibition of angiogenesis through a cascade of pathways is a matter of much research interest. The diverse functions of HRG need to be thoroughly understood. Next, it is essential to know about histidine-rich region (HRR) of histidine-rich glycoprotein (HRG). Its structure comprises of Tandem repeats located in the HRR of cDNA of human HRG and sequences of amino acid derived from it (Alison, Mark and Christopher, 2005).
The residues of amino acid present between 330 and 389 are categorized into a sequence block of five columns and 12 rows(Alison, Mark and Christopher, 2005).This indicates the tandem repeat sequences are harboring conserved HRR (Alison, Mark and Christopher, 2005). In a black back ground, amino acids that are similar to the consensus aminoacid sequence ‘Gly-His-His-Pro-His’ are located. In a sequence block of 15 columns (five codons) and 12 rows, the nucleotides present between 1163 and 1342 are arranged (Alison, Mark and Christopher, 2005).
A consensus sequence ‘GGA CAC CAT CCC CAT’ is present in a black background with the similar nucleotides (Alison, Mark and Christopher, 2005). Further, in the amino acid histidine and HRR of human HRG structure, within the ring structure, the imidazole ring is produced from two nitrogens (Alison, Mark and Christopher, 2005). There are two imidazoles that form the basic metal binding motif (Alison, Mark and Christopher, 2005).
The helical structure of the HRR of HRG is produced such that the imidazole side chains come out from the outer edge of the structure and give rise to several metal binding sites (Alison, Mark and Christopher, 2005). Thus, HRG with its multi domain structural moiety plays role in various biological systems through extracellular adaptor protein (Miri and Yehuda, 1983). Histidine rich region (HRR) has proline link and is known as CDK2/CDK4 (Flodby et al., 1996).
A region belonging to this molecule is known as C/EBPα which is essential for Growth Regulation in Vivo C/EBPα is considered as an important transcription factor that facilitates differentiation of organ systems involving liver, lung, adipose tissue and hematopoietic system (Flodby et al., 1996). The C/EBPα HRR mediates the differentiation process by orchestrating two terminal important events like the gene products upregulation belonging to particular lineage and out ward transit from the cell cycle (Johnson, 2005).
The potential of C/EBPα to mediate arrest of growth has been under study since years (Johnson, 2005). In detail the HRR linked C/EBPα facilitates stabilization of p21 (Timchenko, etal., 1997), employing retinoblastoma (Rb) protein (Porse et al., 2005) and repression of E2F activity (Porse et al., 2001) and diminishing the activity of cyclin-dependent kinase 2 (CDK2)/CDK4. C/EBPα facilitated growth has many standards reflect inhibition and variations in testing systems and, at the organism level indicating that HRR induced C/EBPα may contribute to growth arrest by several approaches in variety of cell types (Wang et al., 1995).
Many experiment al studies employed mouse in elucidating HRR mediated C/EBPα functions (Wang et al., 1995). C/EBPα controls growth in these tissues like liver and lung during late embryonic development. This was revaled when death of null mice was observed following glycogen deficiency and hyperammonemia with many symptoms of hyperplasia (Wang et al., 1995). Earlier, experiments carried out in a knock-in mouse line that has C/EBPα allele (BRM2) lacking E2F repression. (Porse et al., 2001).
These are considered as mutants with no influence on homeostasis and liver development and homeostasis (Porse et al., 2001). Therefore, HRR mediated C/EBPα uses many approaches in several tissues to promote cell cycle exit. HRR plays important role in angiogenesis. It exerts its effects in association with histidine-rich glycoprotein (HRG). Here, Fibroblast growth factor (FGF)-2 erets attached to its cell membrane and induces increased levels of tropomyosin on endothelial cell surface(Alison, Mark and Christopher, 2005). The domain of HRR next attaches to tropomyosin cell surface with an increased affinity and generates antiangiogenic signal that reaches the the endothelial cells(Alison, Mark and Christopher, 2005).
Tropomyosin is deficient in a transmembrane domain, indicating that it needs coreceptor to facilitate the antiangiogenic signal(Alison, Mark and Christopher, 2005). The attachment of HRR to tropomyosin relies on Zn 2+ and pH. Whenever there is physiological pH, HRR binds to tropomyosin and relies on the presence of Zn2+, with increased free Zn2+ local concentrations(Alison, Mark and Christopher, 2005). These are produced from degranulating platelets, even the attachement occurs without Zn2+. Thus the antiangiogenic signal leads to marked apoptosis, low cell proliferation and cell transport(Alison, Mark and Christopher, 2005). These events play important role in the tumor angiogenesis.
This could be because the ligands of HRR linked HRG work in a sequence to promote the binding of various cell surface components to the antiangiogenic factors(Alison, Mark and Christopher, 2005).. HRR of HRG is finely reacts to Ph and Zn2+(Alison, Mark and Christopher, 2005).
This leads to heightened variations in the conformation within the HRR which could be transferred to other domains of the molecule to control their function(Alison, Mark and Christopher, 2005). Therefore, it can be inferred that HRR too constitute the domain of the molecule which attaches with the tumpour cell Tropomyosin causing the synthesis of antiangiogenic signal, indiating that HRG has been demonstrated to bind with several ligands and perform various biological functions(Alison, Mark and Christopher, 2005).
Jose et al (2002) described that the occurrence of endothelial apoptosis is caused by HPRG reflecting the angiogenic phenomenon.
Olsson et al (2004) demonstrate that HRGP when on fragmentation into domains could enable the inhibitory effect related to invivo tumor vascularization indicating the its inhibitory effect on angiogenesis. Poon , Hulett and Parish (2010) further emphasized that the necrotic cell and pathogen exit have resemblance with the immunological output related to the delayed necrotic cell exit. As such HRR is very essential for tumor angiogenesis and has much implications for cancer research.HRR mediated antiangiogenic affect is vital for many invivio interactions of HGRP(Ronit Simantov, et al., 2001).
These include attachment with heparin, metals, and many proteins like thrombospondin-1 (TSP-1), fibrinogen, and plasminogen(Ronit Simantov, et al., 2001). The action of HRGP on TSP-1 was not reported earlier.HRGP binds to TSP-1 which has a 450-kDa homotrimeric adhesive glycoprotein(Ronit Simantov, et al., 2001).
This molecule serves as angiogenesis inhibitor.TSP-1 is produced from the stimulated platelets and several normal vascular cells, like smooth muscle cell and endothelial cells(Ronit Simantov, et al., 2001).It plays important role to diminish the proliferatin of endothelial cell (EC) transport, and tube formation on interaction with several angiogenic stimuli(Ronit Simantov, et al., 2001). TSP-1 with its antiangiogentic functions was reported to be present on structures like properdin-like type I repeats, and synthetic peptides which are formed from the type I domains (Ronit Simantov, et al., 2001).
These all are repoted to have antiangiogenic activity in both assays of EC function and in vivio. HRR and HRGP induced TSP-1 attachment with various cellular receptors is wide spread. But, CD36 has been identified as the severe angiostatic receptor for TSP-1(Ronit Simantov, et al., 2001). The attachment of TSP-1 to CD36 is facilitated through the peptide sequence cysteine-serine-valine-threonine-cysteine-glycine (CSVTCG). This sequence is similar to that of type I repeat described to have antiangiogenic activity(Ronit Simantov, et al., 2001). Thus the structure dependant outcome that greatly facilitates the binding between HRGP and TSP-1 , and the attachment of HRGP presence on type I repeats, similarity in the sequence motifs essential for for CD36 binding are the process tht are important for the HRR and HRGP induced regulation of tumor angiogenesi (Ronit Simantov, et al., 2001).
In view of the above information, Histidine rich glycoprotein (HRGP) is a potent molecule for carrying out various biological functions. Due to the presence of various ligands inherent in its structure, the central core of physiological or homeostatic pathways is becoming an easily manageable functional aspect. Innate immunity much relies on the HRGP as it mediates apoptosis and T cell functions. Complement activation, macrophage stimulation are the important aspects that initiate the process of apoptotic or necrotic particle clearance from the body.
Ivan(2010) described that HRG with special potential binds with IgG and promotes innate immune response of proinflammatory kind to enable the necrotic cell exit.
Lignds like zinc motifs interact at proper physiological conditions like pH to stabilize the concersin of plasminogen. This system known as fibrinolytic system is essential lfor newborns. The plasmin cleaved HRGP contributes to the hygienic blood coagulation system mandatory for newborns. Plasma HRGP levels are considered as important indicators in this regard. Especcially, decreased levels serve as indicators in conditions like sever liver cirrhosis descriebed earlier in children. ATP synthase was also reportd to play vital role in the HRGP induced biological functions. Next ,histidine rich region (HRR) which is part of the HRGP was further implicated in key biological functions smialr to HRGP. It has proline rich motif essential for growth and development
Its interaction with proteins like thrombospondin-1 was implicated much in antiangiognesesis. Therefore, HRGP an HRR are essential components of vital biological functions. There is need to further explore the potential utility of these receptors in an evidence based approach. Much research emphasis should be given to tumor biology in this regard.
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