{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T23:38:03Z","timestamp":1791848283261,"version":"4.3.4"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T00:00:00Z","timestamp":1639612800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The pentraxin family of proteins includes C-reactive protein (CRP), a canonical marker for the acute phase inflammatory response. As compared to normal physiological conditions in human serum, under conditions associated with damage and inflammation, such as acidosis and the oxidative burst, CRP exhibits modulated biochemical properties that may have a structural basis. Here, we explore how pH and ligand binding affect the structure and biochemical properties of CRP. Cryo-electron microscopy was used to solve structures of CRP at pH 7.5 or pH 5 and in the presence or absence of the ligand phosphocholine (PCh), which yielded 7 new high-resolution structures of CRP, including pentameric and decameric complexes. Structures previously derived from crystallography were imperfect pentagons, as shown by the variable angles between each subunit, whereas pentameric CRP derived from cryoEM was found to have C5 symmetry, with subunits forming a regular pentagon with equal angles. This discrepancy indicates flexibility at the interfaces of monomers that may relate to activation of the complement system by the C1 complex. CRP also appears to readily decamerise in solution into dimers of pentamers, which obscures the postulated binding sites for C1. Subtle structural rearrangements were observed between the conditions tested, including a putative change in histidine protonation that may prime the disulphide bridges for reduction and enhanced ability to activate the immune system. Enzyme-linked immunosorbent assays showed that CRP had markedly increased association to the C1 complex and immunoglobulins under conditions associated with acidosis, whilst a reduction in the Ca<jats:sup>2+<\/jats:sup>concentration lowered this pH-sensitivity for C1q, but not immunoglobulins, suggesting different modes of binding. These data suggest a model whereby a change in the ionic nature of CRP and immunological proteins can make it more adhesive to potential ligands without large structural rearrangements.<\/jats:p>","DOI":"10.3389\/fimmu.2021.757633","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T07:47:51Z","timestamp":1639640871000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Cryo-Electron Microscopy and Biochemical Analysis Offer Insights Into the Effects of Acidic pH, Such as Occur During Acidosis, on the Complement Binding Properties of C-Reactive Protein"],"prefix":"10.3389","volume":"12","author":[{"given":"Dylan P.","family":"Noone","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tijn T.","family":"van der Velden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H.","family":"Sharp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nsb0496-346","article-title":"Three Dimensional Structure of Human C-Reactive Protein","volume":"3","author":"Shrive","year":"1996","journal-title":"Nat Struct Biol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0969-2126(99)80023-9","article-title":"The Physiological Structure of Human C-Reactive Protein and Its Complex With Phosphocholine","volume":"7","author":"Thompson","year":"1999","journal-title":"Structure"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.2174\/0929866522666141231111226","article-title":"Staggered Decameric Assembly of Human C-Reactive Protein Stabilized by Zinc Ions Revealed by X-Ray Crystallography","volume":"22","author":"Guillon","year":"2015","journal-title":"Protein Pept Lett"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2004.06.015","article-title":"Structural and Functional Anatomy of the Globular Domain of Complement Protein C1q","volume":"95","author":"Kishore","year":"2004","journal-title":"Immunol Lett"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M307764200","article-title":"The Crystal Structure of the Globular Head of Complement Protein C1q Provides a Basis for Its Versatile Recognition Properties","volume":"278","author":"Gaboriaud","year":"2003","journal-title":"J Biol Chem"},{"key":"B6","doi-asserted-by":"publisher","first-page":"3998","DOI":"10.4049\/jimmunol.166.6.3998","article-title":"Topology and Structure of the C1q-Binding Site on C-Reactive Protein","volume":"166","author":"Agrawal","year":"2001","journal-title":"J Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M504782200","article-title":"Analysis of Binding Sites in Human C-Reactive Protein for Fc\u03b3ri, Fc\u03b3riia, and C1q by Site-Directed Mutagenesis","volume":"280","author":"Bang","year":"2005","journal-title":"J Biol Chem"},{"key":"B8","article-title":"Probing the C1q-Binding Site on Human C-Reactive Protein by Site-Directed Mutagenesis","volume":"1","author":"Agrawal","year":"1994","journal-title":"J Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1172\/JCI18921","article-title":"C-Reactive Protein: A Critical Update","volume":"111","author":"Pepys","year":"2003","journal-title":"J Clin Invest"},{"key":"B10","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/0090-1229(88)90160-2","article-title":"Expression of a C-Reactive Protein Neoantigen (Neo-CRP) in Inflamed Rabbit Liver and Muscle","volume":"48","author":"Rees","year":"1988","journal-title":"Clin Immunol Immunopathol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.20.9.2094","article-title":"C-Reactive Protein in the Arterial Intima: Role of C-Reactive Protein Receptor-Dependent Monocyte Recruitment in Atherogenesis","volume":"20","author":"Torzewski","year":"2000","journal-title":"Ateriosclerosis Thromb Vasc Biol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1084\/jem.114.6.961","article-title":"An Immunohistochemical Method for the Localisation of Cx-Reactive Protein in Rabbits. 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