Models of the complement C1 complex

Mortensen, Simon A.; Sander, Bjørn; Jensen, Rasmus K.; Pedersen, Jan Skov; Golas, Monika M.; Thiel, Steffen; Andersen, Gregers Rom

doi:10.1073/pnas.1803577115

Cited by 3 publications

(5 citation statements)

References 4 publications

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“…The classical pathway begins with activation of the C1 complex, which consists of the sensing molecule C1q and two heterodimers formed by the zymogens C1r and C1s 9 , 14 , 15 . The primary targets of C1q are antigens that, when in complex with IgG1, IgG2 and IgG3 (but not IgG4) or IgM, enable multivalent C1q binding 15 .…”

Section: Main Complement Functionsmentioning

confidence: 99%

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Complement in neurological disorders and emerging complement-targeted therapeutics

2020

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The human complement system is an effector of innate and adaptive humoral immunity. The system comprises soluble membrane-bound proteins (opsonins) that act collectively to recognize pathogens and non-self material and subsequently initiate opsonization and phagocytosis or lysis of pathogens. The proteolytic fragments that derive from complement activation can be targeted by white blood cells and endothelial cells, leading to extravasation and migration of immune cells at the sites of inflammation. Other physiological functions of complement include timely removal of altered and senescent self, tissue remodelling, cell lysis, chemotaxis, opsonization, inflammation and immune cell stimulation 1-4. Complement activation products link the innate and adaptive immune systems by acting directly on receptors on T cells and B cells or by modulating dendritic cell functions 5-8. Disruption of the delicate coordination required for complement activation and control is fundamental in the pathogenic mechanism of several autoimmune neurological disorders, and is even emerging as a contributor in some neurodegenerative diseases. As a result, interest is increasing in targeting complement as a therapeutic approach to prevent ongoing tissue destruction in several difficult-to-treat neurological diseases. In this Review, we provide an overview of the main components of the initial complement activation pathways, the lytic pathway and the factors associated with inappropriate complement activation or control in disease initiation and progression. We consider the role of complement in the tissue destruction that is responsible for the genesis of the most common autoimmune neurological diseases, including complement-mediated myopathies, myasthenia gravis, neuropathies and CNS disorders. We also discuss the role of complement in some neurodegenerative disorders, including Alzheimer disease (AD), amyotrophic lateral sclerosis (ALS), Huntington disease, traumatic brain injury and even schizophrenia. Finally, we discuss emerging complement-targeted therapies, such as monoclonal antibodies, fusion proteins and cyclic peptides, that inhibit the functions of individual complement proteins, especially therapies that disrupt the lytic pathway. Some of these therapeutic agents have been approved or are being tested in phase I-III clinical trials and promise to change the therapeutic armamentarium for treatment of neurological conditions that respond poorly to existing immunotherapies.

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Section: Main Complement Functionsmentioning

confidence: 99%

“…Binding of C1q to its target leads to conformational changes that generate enzymatically active forms of C1r and C1s 13 , 14 , 15 . The resultant C1qC1r 2 C1s 2 enzyme complex mediates cleavage of native C4 followed by cleavage of C2 and the subsequent formation of the C3 convertase C4bC2a.…”

Section: Main Complement Functionsmentioning

confidence: 99%

Complement in neurological disorders and emerging complement-targeted therapeutics

2020

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“…Although each of them is differentially initiated and is characterised by unique and specific factors, they all include the activation of C3 and C5 and lead to a common pathway, which results in the formation of the MAC, ultimately inducing cell lysis by binding to the target cell membrane [11]. The CP is activated by the binding between Immunoglobulins M or G (IgM or IgG), and several other proteins such as C-reactive protein and serum amyloid P protein [12], and C1 complex, which is constituted by the sensing molecule C1q and two heterodimers formed by the zymogens C1r and C1s [12]. C1q activates C1r, which in turn cleaves C1s [13].…”

Section: Complement Pathwaysmentioning

confidence: 99%

Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives

et al. 2021

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The complement system is a key component of innate immunity since it plays a critical role in inflammation and defense against common pathogens. However, an inappropriate activation of the complement system is involved in numerous disorders, including peripheral neuropathies. Current strategies for neuropathy-related pain fail to achieve adequate pain relief, and although several therapies are used to alleviate symptoms, approved disease-modifying treatments are unavailable. This urgent medical need is driving the development of therapeutic agents for this condition, and special emphasis is given to complement-targeting approaches. Recent evidence has underscored the importance of complement component C5a and its receptor C5aR1 in inflammatory and neuropathic pain, indicating that C5a/C5aR1 axis activation triggers a cascade of events involved in pathophysiology of peripheral neuropathy and painful neuro-inflammatory states. However, the underlying pathophysiological mechanisms of this signaling in peripheral neuropathy are not fully known. Here, we provide an overview of complement pathways and major components associated with dysregulated complement activation in peripheral neuropathy, and of drugs under development targeting the C5 system. C5/C5aR1 axis modulators could represent a new strategy to treat complement-related peripheral neuropathies. Specifically, we describe novel C5aR allosteric modulators, which may potentially become new tools in the therapeutic armory against neuropathic pain.

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“…Mortensen et al (1) refer to their earlier analysis of C1 (8). However, this study highlights the dangers of modeling to SAXS data, with insufficient constraints.…”

mentioning

confidence: 76%

“…In their letter, Mortensen et al (1) query our model of zymogen C1. It was assembled from overlapping crystal structures with constraints imposed by known interactions (2).…”

mentioning

confidence: 99%