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Structure, function and control of complement C5 and its proteolytic fragments

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Structure, function and control of complement C5 and its proteolytic fragments. / Laursen, Nick Stub; Magnani, Francesca; Gottfredsen, Randi H; Petersen, Steen V; Andersen, Gregers Rom.

I: Current Molecular Medicine, Bind 12, Nr. 8, 08.09.2012, s. 1083-1097.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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@article{9fa1903b0d57419996267c7d61694060,
title = "Structure, function and control of complement C5 and its proteolytic fragments",
abstract = "As part of the innate immune system, the complement system recognises a wide range of non-self structures present on pathogens or altered self cells. Its activation elicits proteolytic cascades which eventually results in the cleavage of the C5 protein into two fragments, C5a and C5b. The small anaphylatoxin C5a induces a variety of biological responses upon binding to the 7TM receptors C5aR and the C5L2, while the large C5b fragment nucleates formation of the membrane attack complex capable of killing susceptible pathogens by the formation of a pore structure in association with complement components C6, C7, C8, and C9. A number of regulatory molecules help to control C5 mediated immune responses towards host cells, but in several major inflammatory conditions including sepsis and arthritis, C5a is believed to contribute significantly to disease etiology. Inhibition of membrane attack complex assembly is already approved for treatment of paroxysmal nocturnal haemoglobinuria and atypical hemolytic uremic syndrome. A number of recent crystal structures have provided a comprehensive insight into the architecture and properties of intact C5 and its fragments, and how pathogens interfere with their function. Here we review the functional and structural aspects of C5 and its fragments, the pathological conditions associated with them, and strategies employed by pathogens to interfere with the biological function of C5. Structural insight and elucidation of evasion strategies employed by pathogens present a unique opportunity for promoting the development of novel selective C5 inhibitors with therapeutic applications.",
keywords = "Anaphylatoxins, complement, immune evasion, innate immunity, pathogenesis, structural biology, infectious agent, opsonization, phagocytosis, immune complexes, apoptotic cells, zymogens, C-reactive protein, nucleophiles, lectin pathway",
author = "Laursen, {Nick Stub} and Francesca Magnani and Gottfredsen, {Randi H} and Petersen, {Steen V} and Andersen, {Gregers Rom}",
year = "2012",
month = sep,
day = "8",
doi = "10.2174/156652412802480925",
language = "English",
volume = "12",
pages = "1083--1097",
journal = "Current Molecular Medicine",
issn = "1566-5240",
publisher = "Bentham Science Publishers Ltd.",
number = "8",

}

RIS

TY - JOUR

T1 - Structure, function and control of complement C5 and its proteolytic fragments

AU - Laursen, Nick Stub

AU - Magnani, Francesca

AU - Gottfredsen, Randi H

AU - Petersen, Steen V

AU - Andersen, Gregers Rom

PY - 2012/9/8

Y1 - 2012/9/8

N2 - As part of the innate immune system, the complement system recognises a wide range of non-self structures present on pathogens or altered self cells. Its activation elicits proteolytic cascades which eventually results in the cleavage of the C5 protein into two fragments, C5a and C5b. The small anaphylatoxin C5a induces a variety of biological responses upon binding to the 7TM receptors C5aR and the C5L2, while the large C5b fragment nucleates formation of the membrane attack complex capable of killing susceptible pathogens by the formation of a pore structure in association with complement components C6, C7, C8, and C9. A number of regulatory molecules help to control C5 mediated immune responses towards host cells, but in several major inflammatory conditions including sepsis and arthritis, C5a is believed to contribute significantly to disease etiology. Inhibition of membrane attack complex assembly is already approved for treatment of paroxysmal nocturnal haemoglobinuria and atypical hemolytic uremic syndrome. A number of recent crystal structures have provided a comprehensive insight into the architecture and properties of intact C5 and its fragments, and how pathogens interfere with their function. Here we review the functional and structural aspects of C5 and its fragments, the pathological conditions associated with them, and strategies employed by pathogens to interfere with the biological function of C5. Structural insight and elucidation of evasion strategies employed by pathogens present a unique opportunity for promoting the development of novel selective C5 inhibitors with therapeutic applications.

AB - As part of the innate immune system, the complement system recognises a wide range of non-self structures present on pathogens or altered self cells. Its activation elicits proteolytic cascades which eventually results in the cleavage of the C5 protein into two fragments, C5a and C5b. The small anaphylatoxin C5a induces a variety of biological responses upon binding to the 7TM receptors C5aR and the C5L2, while the large C5b fragment nucleates formation of the membrane attack complex capable of killing susceptible pathogens by the formation of a pore structure in association with complement components C6, C7, C8, and C9. A number of regulatory molecules help to control C5 mediated immune responses towards host cells, but in several major inflammatory conditions including sepsis and arthritis, C5a is believed to contribute significantly to disease etiology. Inhibition of membrane attack complex assembly is already approved for treatment of paroxysmal nocturnal haemoglobinuria and atypical hemolytic uremic syndrome. A number of recent crystal structures have provided a comprehensive insight into the architecture and properties of intact C5 and its fragments, and how pathogens interfere with their function. Here we review the functional and structural aspects of C5 and its fragments, the pathological conditions associated with them, and strategies employed by pathogens to interfere with the biological function of C5. Structural insight and elucidation of evasion strategies employed by pathogens present a unique opportunity for promoting the development of novel selective C5 inhibitors with therapeutic applications.

KW - Anaphylatoxins

KW - complement

KW - immune evasion

KW - innate immunity

KW - pathogenesis

KW - structural biology

KW - infectious agent

KW - opsonization

KW - phagocytosis

KW - immune complexes

KW - apoptotic cells

KW - zymogens

KW - C-reactive protein

KW - nucleophiles

KW - lectin pathway

U2 - 10.2174/156652412802480925

DO - 10.2174/156652412802480925

M3 - Journal article

C2 - 22812419

VL - 12

SP - 1083

EP - 1097

JO - Current Molecular Medicine

JF - Current Molecular Medicine

SN - 1566-5240

IS - 8

ER -