The cholesterol binding sequences are near the PC binding sites so that when pCRP binds membrane associated PC, the cholesterol binding sequence is brought into proximity with intra-membraneous cholesterol (in lipid rafts) contributing to the conversion of pCRP into mCRP. The PC ligand binds in a shallow binding pocket controlled by calcium ions, with all PC sites on one face of the flattened discoid structure. (C) shows the orientation of same sequences on the isolated pCRP subunit (note: the exact orientation of these residues on the conformationally changed mCRP subunit has not been determined). (B) illustrates the orientation of these same residues when the discoid protein is laid flat (i.e. (A) illustrates the location and orientation peptide sequences in CRP reported to have cell-binding activity (shown in yellow and involving 27TKPLKAFTVCLH 38) (105), anti-cancer activity (shown in blue and involving 176LGGPFSPNVL 185) (106), cholesterol binding activity (shown in red and involving 35VCLHFYTELSSTR 47), and which also controls CRP binding to apolipoprotein B, C1q, fibronectin, and collagen (107), in relationship to the phosphocholine (PC) binding face (PC groups shown in gray and involving residues L 64, F 66, and T 76) and bound calcium ions (two per subunit, juxtaposed to each PC binding sites and involves residue E 147) (PDB code: 1B09 PC and calcium residues as defined by Thompson et al. Structural features of serum-soluble pentameric CRP. Herein, a novel interpretation of the diagnostic utility of CRP is presented accounting for the unique properties of the CRP isoforms in the context of the developing pro-metastatic tumor microenvironment.Ĭ-reactive protein acute phase response inflammation monomeric C-reactive protein tumor microenvironment.Ĭopyright © 2020 Hart, Rajab, Alebraheem and Potempa. Its accumulation in blood is associated with a continuous, low-level inflammatory response and is indicative of unresolved and advancing disease, as occurs in cancer. Conversely, CRP in its pentameric isoform (pCRP), which is the form quantified in diagnostic measurements of CRP, is notably less bioactive with weak anti-inflammatory bioactivity. It also binds components of the extracellular matrix in involved tissues. CRP in its monomeric, modified isoform (mCRP) modulates inflammatory responses by inserting into activated cell membranes and stimulating platelet and leukocyte responses associated with acute phase responses to tumor growth. By considering the recent understanding that CRP exists in multiple isoforms with distinct biological activities, a unified model is advanced that describes the relevance of CRP as a mediator of host defense responses in cancer. Its diagnostic significance in assessing disease progression or remission, however, remains undefined. C-reactive protein (CRP) is a predominant protein of the acute phase response its blood levels have long been used as a minimally invasive index of any ongoing inflammatory response, including that occurring in cancer. As tumors grow and metastasize, they affect normal tissue integrity and homeostasis which signals the body to trigger the acute phase inflammatory response. As cells duplicate, they can remain localized in defined tissues, forming tumor masses and altering their microenvironmental niche, or they can disseminate throughout the body in a metastatic process affecting multiple tissues and organs. Cancer disease describes any pathology involving uncontrolled cell growth.
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