A type III complement factor D deficiency: Structural insights for inhibition of the alternative pathway

Conversely, in both mutant simulations, the distance remained larger, consistent with His41 pointing away from the active site. [...]in addition to disruption of key FB-binding residues, mutations R176P and R176A appear to stabilize the self-inhibited conformation of free FD. Overactivation of AP is...

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Published inJournal of allergy and clinical immunology Vol. 142; no. 1; pp. 311 - 314.e6
Main Authors Sng, Christopher C.T., O'Byrne, Sorcha, Prigozhin, Daniil M., Bauer, Matthias R., Harvey, Jennifer C., Ruhle, Michelle, Challis, Ben G., Lear, Sara, Roberts, Lee D., Workman, Sarita, Janowitz, Tobias, Magiera, Lukasz, Doffinger, Rainer, Buckland, Matthew S., Jodrell, Duncan J., Semple, Robert K., Wilson, Timothy J., Modis, Yorgo, Thaventhiran, James E.D.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 01.07.2018
Elsevier Limited
Mosby
Subjects
Alternative pathway
Complement factor D
Complement Factor D - chemistry
Complement Factor D - deficiency
Complement Factor D - genetics
Complement Pathway, Alternative
Female
Hereditary Complement Deficiency Diseases
Humans
Immunologic Deficiency Syndromes - genetics
Inflammatory diseases
Macular degeneration
Male
Metabolism
Mutation
Pedigree
Protein Conformation
Simulation
Young Adult
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Summary:Conversely, in both mutant simulations, the distance remained larger, consistent with His41 pointing away from the active site. [...]in addition to disruption of key FB-binding residues, mutations R176P and R176A appear to stabilize the self-inhibited conformation of free FD. Overactivation of AP is implicated in numerous inflammatory disorders, including age-related macular degeneration. [...]blockade of the AP by targeting the rate-limiting enzyme, FD, is an attractive approach to controlling disease progression. Furthermore, circulating concentrations of leptin and adiponectin, adipokines that regulate insulin sensitivity, were normal, as were fasting lipid profiles in both subjects. [...]glucose homeostasis is not impaired in the context of genetic, and therefore lifelong, FD deficiency. [...]research will be required to understand the role of FD in glucose homeostasis and FD-deficient family pedigrees offer a useful clinical insight to this question.Methods Informed consent statement All study participants gave their informed consent as appropriate under approved protocols from local institutional review boards.
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These authors contributed equally to this work.
ISSN:0091-6749
1097-6825
1097-6825
DOI:10.1016/j.jaci.2018.01.048