{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:38:01Z","timestamp":1791848281126,"version":"4.3.4"},"reference-count":112,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T00:00:00Z","timestamp":1662595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>Early purification protocols for C-reactive protein (CRP) often involved co-isolation of lipoproteins, primarily very low-density lipoproteins (VLDLs). The interaction with lipid particles was initially attributed to CRP\u2019s calcium-dependent binding affinity for its primary ligand\u2014phosphocholine\u2014the predominant hydrophilic head group expressed on phospholipids of most lipoprotein particles. Later, CRP was shown to additionally express binding affinity for apolipoprotein B (apo B), a predominant apolipoprotein of both VLDL and LDL particles. Apo B interaction with CRP was shown to be mediated by a cationic peptide sequence in apo B. Optimal apo B binding required CRP to be surface immobilized or aggregated, treatments now known to structurally change CRP from its serum soluble pentamer isoform (i.e., pCRP) into its poorly soluble, modified, monomeric isoform (i.e., mCRP). Other cationic ligands have been described for CRP which affect complement activation, histone bioactivities, and interactions with membranes. mCRP, but not pCRP, binds cholesterol and activates signaling pathways that activate pro-inflammatory bioactivities long associated with CRP as a biomarker. Hence, a key step to express CRP\u2019s biofunctions is its conversion into its mCRP isoform. Conversion occurs when (1) pCRP binds to a membrane surface expressed ligand (often phosphocholine); (2) biochemical forces associated with binding cause relaxation\/partial dissociation of secondary and tertiary structures into a swollen membrane bound intermediate (described as mCRP<jats:sub><jats:italic>m<\/jats:italic><\/jats:sub>or pCRP*); (3) further structural relaxation which leads to total, irreversible dissociation of the pentamer into mCRP and expression of a cholesterol\/multi-ligand binding sequence that extends into the subunit core; (4) reduction of the CRP subunit intrachain disulfide bond which enhances CRP\u2019s binding accessibility for various ligands and activates acute phase proinflammatory responses. Taken together, the biofunctions of CRP involve both lipid and protein interactions and a conformational rearrangement of higher order structure that affects its role as a mediator of inflammatory responses.<\/jats:p>","DOI":"10.3389\/fcvm.2022.979461","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T06:02:04Z","timestamp":1662616924000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Relevance of lipoproteins, membranes, and extracellular vesicles in understanding C-reactive protein biochemical structure and biological activities"],"prefix":"10.3389","volume":"9","author":[{"given":"Lawrence A.","family":"Potempa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei Qiao","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"Stefanski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibraheem M.","family":"Rajab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/0022-1759(78)90203-X","article-title":"C-reactive protein: purification by affinity chromatography and physicochemical characterization.","volume":"23","author":"Volanakis","year":"1978","journal-title":"J Immuno Meth."},{"key":"B2","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/281155a0","article-title":"Interaction of C-reactive protein with artificial phosphatidylcholine bilayers.","volume":"281","author":"Volanakis","year":"1979","journal-title":"Nature."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.3389\/fimmu.2018.01089","article-title":"pCRP-mCRP dissociation mechanisms as potential targets for the development of small-molecule anti-inflammatory chemotherapeutics.","volume":"9","author":"Caprio","year":"2018","journal-title":"Front Immunol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1007\/s41048-020-00108-9","article-title":"C-reactive protein in gallbladder diseases \u2013 diagnostic and therapeutic insights.","volume":"6","author":"Rajab","year":"2020","journal-title":"Biophys Rep."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e1409","DOI":"10.14800\/ics.1409","article-title":"The role of C-reactive protein in innate and acquired inflammation: new perspectives.","volume":"3","author":"Trial","year":"2016","journal-title":"Inflammation Cell Signal."},{"key":"B6","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/0022-1759(93)90333-3","article-title":"A capillary electrophoresis-based assay for the binding of Ca2+ and phosphorylcholine to human C-reactive protein.","volume":"166","author":"Heegaard","year":"1993","journal-title":"J Immunol Methods."},{"key":"B7","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.ab.2009.04.037","article-title":"Characterization of Ca2+ and phosphocholine interactions with C-reactive protein using a surface plasmon resonance biosensor.","volume":"391","author":"Christopeit","year":"2009","journal-title":"Anal Biochem."},{"key":"B8","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1002\/jmr.1090","article-title":"Structural basis of ligand specificity in the human pentraxins, C-reactive protein and serum amyloid P component.","volume":"24","author":"Mikolajek","year":"2011","journal-title":"J Mol Recognit."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.21203\/rs.3.rs-944388\/v1","author":"Zeller","year":"2021","journal-title":"Discovery, in-vitro, and in-vivo efficacy of an anti-inflammatory small molecule inhibitor of C-reactive protein. 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