Molecular mechanism of sialic-acid mediated self-recognition by complement factor H
Biochemistry
Structural Biology
Final Report Abstract
In the course of this project a comprehensive elucidation of the complement factor H (FH)- sialic acid recognition process was achieved. It was found that FH contains a single sialic acid binding site, that this site is specific for α2-3-linked sialic acid, that the protein can bind linear and branched glycans and also the non-human sialic acid variant α-N-glycolylneuraminic acid. It was further shown that FH does likely not interact with its own sialylation, which is present in the form of eight N-glycosylation chains mostly capped by α2-6-linked sialic acid - excluding this possibility as a means of FH regulation on host surfaces. The physiological relevance of our findings, apart from the fundamental research aspects, concern two distinct medical fields. On the one hand, our work suggested a molecular basis of the hereditary disease atypical hemolytic uremic syndrome (aHUS) (there are several molecular causes for this disease, with impaired sialic acid recognition being one of them). On the other hand, human infection by certain Neisseria strains which use a sialylated „cover“ as a means for immune evasion is also linked to our discovery. Our structural biology findings suggested mechanistic explanations for both physiological observations and were confirmed by other researchers focussing on complement-linked diseases and pathological Neisseria gonorrhoeae strains, respectively. On a more technical note, we also discovered a novel conformation of the GM1 glycan (bound by FH), with methodological implications for the field not so much of complement research but glycobiology.
Publications
- Complement Factor H and Simian Virus 40 bind the GM1 ganglioside in distinct conformations. Glycobiology 2016; 26(5):532-9
Blaum BS, Frank M, Walker RC, Neu U, Stehle T
(See online at https://doi.org/10.1093/glycob/cwv170) - The lectin self of complement factor H. Curr Opin Struct Biol 2017; 44:111-118
Blaum BS
(See online at https://doi.org/10.1016/j.sbi.2017.01.005) - Biophysical analysis of sialic acid recognition by the complement regulator Factor H. Glycobiology 2018; 28(10):765-773
Schmidt CQ, Hipgrave Ederveen AL, Harder MJ, Wuhrer M, Stehle T, Blaum BS
(See online at https://doi.org/10.1093/glycob/cwy061)
