User:Matthew Chien/Sandbox 1

Introduction

Complement component 1q, or , is the first component of the classical pathway of the complement system. C1q is a subcomponent of the Complement component 1 (C1), along with C1r and C1s. C1q consists of six globular-head regions all connected to a collagen-like region (), with each globular head consisting of 3 separate , having a total mass of roughly 460 kDa. The activation of C1q through the binding of the globular head to a variety of epitopes induces structural changes in the collagen-like region of C1q. This activates C1r, which cleaves C1s, which splits into other complement proteins to further activate other aspects of the classical complement system pathway. C1q binds to a variety of different antigens, such as phagocytes to induce phagocytosis, apoptotic cells through phosphatidylserine and DNA to induce apoptosis, and the Fc region of IgG and IgM to activate the complement system as described. C1q acts as a crucial protein that bridges the adaptive and innate immune system.

Function

Innate Immunity

C1q plays a major role in the innate part of the immune system. It is the first complement protein to be activated in the classical complement pathway. This pathway of complement activation is dependent on the detection of antibody-antigen complexes, which creates a cascade of complement protein activation to ultimately promote inflammation, enhance the performance of various immune cells, and attack the pathogen's cell membrane. This acts as an irreplicable aspect of the innate immune system and is one of the body's primary defense against invaders.

C1q is also known to be a kind of opsonin, which is a protein that tags a foreign cell to be engulfed and destroyed by phagocytes, such as neutrophils and macrophages. This process is a very important aspect of the innate immune system to eliminate foreign bacteria and viruses to keep the host healthy. It has been shown that both neutrophils and macrophages posses receptors capable of binding the globular head and CLR of C1q, named gC1q and cC1q respectively, emphasizing their crucial role for phagocytes to identify and eliminate foreign pathogens. Immature dendritic cells have also been shown to contain a large amounts of gC1q and cC1q. This acts as an important bridge between the innate and adaptive immune systems; dendritic cells can survey certain areas based on the amount of present C1q in order to activate and begin digesting antigens to present to T-cells, which is a crucial step in adaptive immunity activation.

Adaptive Immunity

As iterated above, C1q is important in the activation phase of the adaptive immune response. In addition, C1q plays a major role in the solubilization of certain immune complexes, mainly the antibody-antigen complex. One of the main roles of C1q is to bind to these complexes at the Fc region of Immunoglobulin (Ig) G and IgM when bonded to an antigen. This activates the classical cascade of the complement system but also prevents the immune complex from becoming insoluble, which could lead to further unnecessary inflammation as they can no longer be detected by phagocytes for destruction. C1q, especially the globular head region, is known to be profoundly and is a key component in the prevention of preformed immune precipitation, along with other components of the classical complement pathway.

C1q has been shown to partially facilitate the function of T-cells. The receptors gC1q and cC1q are both present on T-cells and serve as both activators and inhibitors. In the presence of immune complexes, C1q has shown to activate T-cells, acting as a bridge between the innate and adaptive immune system. In terms of inhibition, C1q is observed to suppress the activity of T-cells in certain environments to regulate the immune system and prevent autoimmune disease. C1q is known to bind to various phospholipids, namely phosphatidylserine, which is largely present on the surface of apoptotic cells. This promotes opsonization by complement proteins such as C1q which leads to macrophage activation while also inhibiting T-cells to interact with the apoptotic cells. Over-activation of T-cells can lead to unnecessary harm within the body when their presence is not necessary and phagocytes are favored.

Active Site

Globular Head

C1q is observed to have many active sites depending on what it is interacting with, with most of these active sites being located on the globular head regions. The most researched interaction concerning C1q active site is its interaction with the antibody-antigen complex. C1q largely depends on ionic residues to create salt bridges and ionic bonds with the Cγ2 domain of IgG or the Cμ3 domain of IgM. The Cγ2 of IgG is located on the Fc region, which becomes aggregated upon complexing with antigens, allowing for increased affinity to C1q. Residues Glu198 -X- Asp200 -X- Lys202 on the A chain of the C1q globular head have been shown to be a consistent active site motif on C1q. This region forms an antiparallel ß-sheet, promoting stability. Another active site has been observed on the B chain of the globular head region (ghB) at residues 114-129. The principle residues involved in binding are the Arg114 and Arg129. These residues interact with negatively charged residues on IgG, mostly Asp and Glu, such as residues Glu195 and Glu287. A common motif seen on IgG that these active sites interact with is Glu - X - Lys - X - Lys, located at residues 318, 320, and 322 respectively. This is a common motif seen on many proteins associated with the immune system, which enforces the observation that C1q can interact with many different proteins in many different contexts. One study showed that an arginine or lysine is required at positions 320 and 322 and a glutamic acid or threonine is required at position 318 in order for C1q to successfully bind. This suggests that a hydrogen bond at position 318 and an ionic interaction at positions 320 and 322 are required for C1q to bind to IgG and other epitopes.

Collagen-Like Region

Disease

Structural highlights