C3

Official Full Name

complement C3

Organism

Homo sapiens

GeneID

718

Background

Complement component C3 plays a central role in the activation of complement system. Its activation is required for both classical and alternative complement activation pathways. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that form the mature protein, which is then further processed to generate numerous peptide products. The C3a peptide, also known as the C3a anaphylatoxin, modulates inflammation and possesses antimicrobial activity. Mutations in this gene are associated with atypical hemolytic uremic syndrome and age-related macular degeneration in human patients. [provided by RefSeq, Nov 2015]

Synonyms

ASP; C3a; C3b; AHUS5; ARMD9; CPAMD1; HEL-S-62p;

Bio Chemical Class

Complement system

Protein Sequence

MGPTSGPSLLLLLLTHLPLALGSPMYSIITPNILRLESEETMVLEAHDAQGDVPVTVTVHDFPGKKLVLSSEKTVLTPATNHMGNVTFTIPANREFKSEKGRNKFVTVQATFGTQVVEKVVLVSLQSGYLFIQTDKTIYTPGSTVLYRIFTVNHKLLPVGRTVMVNIENPEGIPVKQDSLSSQNQLGVLPLSWDIPELVNMGQWKIRAYYENSPQQVFSTEFEVKEYVLPSFEVIVEPTEKFYYIYNEKGLEVTITARFLYGKKVEGTAFVIFGIQDGEQRISLPESLKRIPIEDGSGEVVLSRKVLLDGVQNPRAEDLVGKSLYVSATVILHSGSDMVQAERSGIPIVTSPYQIHFTKTPKYFKPGMPFDLMVFVTNPDGSPAYRVPVAVQGEDTVQSLTQGDGVAKLSINTHPSQKPLSITVRTKKQELSEAEQATRTMQALPYSTVGNSNNYLHLSVLRTELRPGETLNVNFLLRMDRAHEAKIRYYTYLIMNKGRLLKAGRQVREPGQDLVVLPLSITTDFIPSFRLVAYYTLIGASGQREVVADSVWVDVKDSCVGSLVVKSGQSEDRQPVPGQQMTLKIEGDHGARVVLVAVDKGVFVLNKKNKLTQSKIWDVVEKADIGCTPGSGKDYAGVFSDAGLTFTSSSGQQTAQRAELQCPQPAARRRRSVQLTEKRMDKVGKYPKELRKCCEDGMRENPMRFSCQRRTRFISLGEACKKVFLDCCNYITELRRQHARASHLGLARSNLDEDIIAEENIVSRSEFPESWLWNVEDLKEPPKNGISTKLMNIFLKDSITTWEILAVSMSDKKGICVADPFEVTVMQDFFIDLRLPYSVVRNEQVEIRAVLYNYRQNQELKVRVELLHNPAFCSLATTKRRHQQTVTIPPKSSLSVPYVIVPLKTGLQEVEVKAAVYHHFISDGVRKSLKVVPEGIRMNKTVAVRTLDPERLGREGVQKEDIPPADLSDQVPDTESETRILLQGTPVAQMTEDAVDAERLKHLIVTPSGCGEQNMIGMTPTVIAVHYLDETEQWEKFGLEKRQGALELIKKGYTQQLAFRQPSSAFAAFVKRAPSTWLTAYVVKVFSLAVNLIAIDSQVLCGAVKWLILEKQKPDGVFQEDAPVIHQEMIGGLRNNNEKDMALTAFVLISLQEAKDICEEQVNSLPGSITKAGDFLEANYMNLQRSYTVAIAGYALAQMGRLKGPLLNKFLTTAKDKNRWEDPGKQLYNVEATSYALLALLQLKDFDFVPPVVRWLNEQRYYGGGYGSTQATFMVFQALAQYQKDAPDHQELNLDVSLQLPSRSSKITHRIHWESASLLRSEETKENEGFTVTAEGKGQGTLSVVTMYHAKAKDQLTCNKFDLKVTIKPAPETEKRPQDAKNTMILEICTRYRGDQDATMSILDISMMTGFAPDTDDLKQLANGVDRYISKYELDKAFSDRNTLIIYLDKVSHSEDDCLAFKVHQYFNVELIQPGAVKVYAYYNLEESCTRFYHPEKEDGKLNKLCRDELCRCAEENCFIQKSDDKVTLEERLDKACEPGVDYVYKTRLVKVQLSNDFDEYIMAIEQTIKSGSDEVQVGQQRTFISPIKCREALKLEEKKHYLMWGLSSDFWGEKPNLSYIIGKDTWVEHWPEEDECQDEENQKQCQDLGAFTESMVVFGCPN

Open

Disease

Breast cancer, Colorectal cancer, Gingival disease, Haemolytic anemia, Head and neck cancer, Macular degeneration, Malignant haematopoietic neoplasm, Melanoma, Retinopathy

Approved Drug

1 +

Clinical Trial Drug

5 +

Discontinued Drug

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Detailed Information

Representing a necessary component of innate immunity, the complement system bridges innate and adaptive immune responses and offers quick and efficient defense against infections. Complement component C3, a protein whose structural intricacy and functional adaptability make it a model of nature's inventiveness in immune defense design, forms the core of this system. Originally noted as a heat-labile component of serum that "complemented" antibodies in bacterial lysis, C3 has become a major actor in many physiological processes outside of conventional immunity.

Molecular Architecture and Evolution

The complicated functional needs of C3 are reflected in its molecular architecture. Comprising α and β chains organized in an elegant shape honed over millions of years of evolution, C3 is a big protein of 187 kDa. Eight macroglobulin domains make up the core of the protein; six of them create a ring-like shape. Over 1.3 billion years, this evolutionary trip has produced a highly conserved molecule with several uses that preserve exact control. Key domains—the CUB domain, the anaphylatoxin domain, and the thioester-containing domain (TED)—added by gene insertion events have improved C3's functional repertoire even further.

This intricate design allows C3 to stay inactive until required, therefore reflecting the exact control inherent in complement activation. Particularly the hiding of the thioester group between TED and the macroglobulin domains guarantees the strategic orientation of domains that guarantee C3 activation only under certain conditions.

Activation and Amplification

A turning point in the complement cascade, the activation of C3 acts as a convergence point for many pathways and starts a fast amplification response. Several processes underlie this process, each designed to identify distinct hazards to the host. Specific recognition molecules attaching to pathogen surfaces or immune complexes starts the classical and lectin pathways, which produce C3 convertases cutting C3 into its active pieces.

One special property of C3 is its capacity to start complement activation by means of "tick-over," or spontaneous hydrolysis. Constant low-level observation made possible by this system enables fast reaction to any hazards. Once triggered, C3b reveals its reactive thioester group, allowing covalent attachment to surrounding surfaces and starting a strong amplification loop capable of contributing up to 80% of the total complement response even in cases of initiation by alternative paths.

Functional Diversity of C3 Fragments

C3's cleavage produces fragments with different and strong biological activity, each of which adds in different ways to the total immune response. The main opsonin, C3b, has many roles: it generates additional C3 convertases to drive the amplification loop, designates phagocytosis targets, facilitates immunological adherence via contact with complement receptors, and helps to modulate adaptive immunity. With their distinct functional characteristics, the controlled degradation of C3b yields iC3b and C3dg. While C3dg affects B cell responses and preserves certain phagocytic capacities, iC3b increases phagocytosis via interactions with several complement receptors and participates in developmental processes.

Once thought to as just a mild anaphylatoxin, the tiny peptide C3a has become a vital signaling molecule with several purposes. Beyond its involvement in inflammation, C3a drives hematopoietic stem cell homing, helps tissues grow and regenerate, and could potentially act as an antimicrobial peptide. These many functions underline the amazing adaptability of C3 and its components in homeostasis and immunological defence.

Figure 1 illustrates the various roles of C3 in complement activation and effector functions, highlighting its pathways, mechanisms, and effector functions in immune responses. Figure 1. Roles of C3 in complement activation and effector functions. (Ricklin D, et al., 2016)

Regulation and Clinical Implications

The strength of C3-mediated reactions calls for strict control to avoid harm to host tissue. Soluble as well as membrane-bound proteins cooperate to regulate C3 activation and function. Among the many ways these controllers work are acceleration of C3 convertase decay and enhancement of C3b degradation. The link of C3 malfunction with many diseases, including atypical hemolytic uremic syndrome and age-related macular degeneration, emphasizes the need for appropriate C3 control.

Knowing the intricate biology of C3 has given fresh treatment opportunities because scientists investigate methods to control its activity in different illness environments. A fascinating prospect in complement-targeted treatments is the discovery of C3 inhibitors and techniques for focused control of certain C3 activities.

Future Perspectives

Complement component C3 provides evidence of the intelligence of natural immunity. It is very essential for host defence as it may start, magnify, control immune reactions and produce different effector molecules. Recent findings of C3's participation in mechanisms outside of conventional immunity emphasise the importance of ongoing study of this flexible protein. Our knowledge of C3 biology is growing, and along with it our respect of this amazing molecule and its potential therapeutic target in many illnesses. Future research aiming on clarifying tissue-specific activities of C3 and designing more focused therapy strategies will surely expose even more aspects of this interesting protein.

References:

Ricklin D, Reis ES, Mastellos DC, et al. Complement component C3 - The "Swiss Army Knife" of innate immunity and host defense. Immunol Rev. 2016;274(1):33-58.
Geisbrecht BV, Lambris JD, Gros P. Complement component C3: A structural perspective and potential therapeutic implications. Semin Immunol. 2022. Epub 2022 Jun 25.
Zarantonello A, Revel M, Grunenwald A, et al. C3-dependent effector functions of complement. Immunol Rev. 2023 Jan;313(1):120-138.

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