Complement Nomenclature-Deconvoluted

Abstract

In 2014, specific recommendations for complement nomenclature were presented by the complement field. There remained some unresolved designations and new areas of ambiguity, and here we propose solutions to resolve these remaining issues. To enable rapid understanding of the intricate complement system and facilitate therapeutic development and application, a uniform nomenclature for cleavage fragments, pattern recognition molecules (PRMs) and enzymes of the lectin pathway and regulatory proteins of the complement system are proposed, and a standardization of language to designate different activation states of complement components is recommended.

Keywords: C1; C1q; C2; clusterin; collectins; complement; lectin pathway; nomenclature.

Figure 1

(A) Complement activities control key cellular processes and contribute to a broad range of disease states. It is now broadly acknowledged that complement functions well beyond mere protection against invading pathogens but participates actively in the control of key physiological processes. Therefore, complement is key to normal cell and tissue homeostasis and aberrant complement activation (either too little or too much) can hence cause or contribute to a broad range of disease settings including recurrent infections and cancer (too little) or auto-immunity and fibrosis (too much). (B) Schematic representation of C3 family members, FB, and C2. While convention holds that smaller fragments (yellow for C3, C4, C5, and FB) retain earlier letters than larger fragments (Blue for C3, C4, C5, and FB), C2 breaks with convention (C2 current). To facilitate communication in the field and better standardize complement nomenclature, we recommend adopting standard convention for C2 (C2 recommended). (▾) Indicates cleavage site for liberation of smaller fragment. (C) C1 is a complex macromolecular structure consisting of C1q, C1r, and C1s. C1 circulates in blood as an “unactivated” complex of the recognition protein, C1q (yellow), and two molecules each of the proenzymes C1r and Cls (blue and green ellipses). Conformational changes induced by binding to an activator result in activated C1 due to the conversion of C1r and C1s to active serine proteases (blue and green triangles). C1s proceeds to cleave C4 and C2 which results ultimately in the formation of the classical pathway C3 convertase, C4b2b. Generation of opsonic C3b and iC3b, and subsequently C5a and C5b-9 (not shown) mediate the possible complement effector functions that follow. Four C1-INH molecules per C1 (only representative complexes are shown) are required to inactivate the serine proteases, C1r and C1s, and results in their dissociation from C1q, thereby regulating the amount of C4b2b generated. In the lower row, C1q can be synthesized in tissue to “silently” eliminate apoptotic cells and cellular debris.