Complement Regulator of Complement System: Complement Component Factor H

Complement factor H is a soluble complement regulator necessary for controlling the alternative pathway in blood and on cell surfaces. More than 40 years after its initial discovery, factor H still has many secrets to reveal. Here, Creative Biolabs has brought a wealth of information on factor H.

Structure and Function of Factor H

Factor H is one of the main soluble regulators of the alternative complement pathway. The factor H gene (CFH) is located on chromosome 1q32 in the regulators of complement activation (RCA) gene cluster. Factor H, constitutively expressed in the liver and distributed systemically in body fluids, is produced by different cell types such as fibroblasts, monocytes, keratinocytes and endothelial cells. Factor H is a single-chain, 150 kDa plasma glycoprotein composed of 20 domains termed complement control protein modules (CCPs). Each of CCP domain is composed of almost 60 amino acids (aa) and is stabilized by two internal disulfide-bonds. Factor H regulates complement activation by the following three mechanisms:

  1. Inhibiting the assembly of the alternative pathway C3 and C5 convertase enzymes viacompetition with factor B for C3b binding.
  2. Facilitating the disassembly of the convertases by displacing bound factor Bb -decay accelerating activity.
  3. Acting as a cofactor for the serine protease factor I in the cleavage and inactivation of C3b-cofactor activity.

These regulatory activities are mediated by the four N-terminal domains CCP 1-4, while the C-terminal domains CCPs 19-20 are responsible for target recognition. One of the important targets for factor H binding in the vicinity of C3b on host cells are polyanionic surface molecules which increase the affinity of factor H for C3b. Therefore, in addition to its regulatory activities in the fluid phase, factor H is also able to control complement activation on self-surfaces.

The schematic structure of factor H

Fig.1 The schematic structure of factor H. (Kopp, 2012)

Factor H Interactions with Host Ligands

  1. Factor H Interaction with C3b

The central complement protein C3b is the main host ligand of factor H. The C3b-factor H interaction is of particular importance for the pivotal functions of factor H. In factor H, 4 binding sites were reported for C3b and its fragments. These binding sites are located in the CCP domains 1-4, 6-8, 12-14 and 19-20. Each with a different binding preference, affinity and functional relevance.

  1. Factor H Attachment to Host Cells

Besides membrane-bound regulators, host cells require soluble complement inhibitors, particularly factor H to provide effective protection from unwanted complement-mediated damage.

  1. Factor H Binding to Extracellular Matrix (ECM)

It was shown that the ECM proteins such as osteoadherin, fibromodulin and chondroadherin can bind both C1q and the regulators factor H and C4b-binding protein, maintaining a balance between complement activation and inhibition.

Overview of main factor H functions and their implication in pathological conditions

Fig.2 Overview of main factor H functions and their implication in pathological conditions. (Kopp, 2012)

Factor H Deficiency

Analysis of the genetic defects leading to complete deficiency of factor H in plasma of patients revealed homozygous or compound heterozygous factor H gene mutations in CCPs 2, 4, 9, 11, and 16, which result in non-framework amino acid exchanges or in mutations of framework Cys residues affecting disulphide bond formation within the factor H molecule. All these mutations result in a block of protein secretion: the mutant protein is expressed in hepatocytes but is retained in the endoplasmic reticulum, thereby accumulating in the cytoplasm. As a consequence, absence of factor H in plasma causes sustained activation of the alternative complement pathway.

Factor H-related diseases:

  1. The common factor H polymorphism 402H has been identified as a major genetic risk factor for developing age-related macular degeneration (AMD). Besides, a protective CFH haplotype associated with the deletion of the CFHR1 and CFHR3 genes in AMD has been described.
  2. Factor H mutations affect approximately 30% of Hemolytic Uremic Syndrome (HUS) patients and anti-factor H IgG autoantibodies are detected in approximately 10% of HUS patients.
  3. Dense deposit disease (DDD) is a disease associated with uncontrolled alternative pathway activation in plasma that generates C3 activation fragments depositing in the glomeruli. Factor H mutations have been identified in some DDD patients. These mutations may lead to factor H deficiency and thus an insufficient plasma complement control.

Creative Biolabs offers a full range of complement component CFH-related services and products, including:

  1. CFH Antibodies
  2. CFH Related Array Kits
  3. Peptides
  4. Lysates

Reference

  1. Kopp, A.; et al. Factor h: a complement regulator in health and disease, and a mediator of cellular interactions. Biomolecules. 2012, 2(1): 46-75.

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