The four terminal components of the complement system are C-mannosylated on multiple tryptophan residues.
C-Mannosylation is a unique form of protein glycosylation, involving the C-glycosidic attachment of a mannosyl residue to the indole moiety of Trp. In the two examples found so far, human RNase 2 and interleukin-12, only the first Trp in the recognition motif WXXW is specifically C-mannosylated. To establish the generality of protein C-mannosylation, and to learn more about its mechanism, the terminal components of the human complement system (C6, C7, C8,and C9), which contain multiple and complex recognition motifs, were examined. Together with C5b they form the cytolytic agent, the membrane attack complex. These are the first proteins that are C-mannosylated on more than one Trp residue as follows: six in C6, four in C7, C8alpha, and C8beta, and two in C9. Thus, from the 113 Trp residues in the complete membrane attack complex, 50 were found to undergo C-mannosylation. The other important finding is that in C6, C7, C8, and C9 Trp residues without a second Trp (or another aromatic residue) at the +3 position can be C-mannosylated. This shows that they must contain an additional C-mannosylation signal. Whether this is encoded in the primary or tertiary structure is presently unknown. Finally, all modified Trp residues are part of the highly conserved core of the thrombospondin type 1 repeats present in these proteins. Since this module has been found in a large number of other proteins, the results suggest further candidates for C-mannosylation.
Hofsteenge
J
J
Friedrich Miescher-Institut, Switzerland. hofsteen@fmi.ch
Blommers
M
M
Hess
D
D
Furmanek
A
A
Miroshnichenko
O
O
D015938:Complement Membrane Attack Complex / Q000737:chemistry*; D006020:Glycopeptides / Q000737:chemistry; D006023:Glycoproteins / Q000737:chemistry; D006031:Glycosylation; D006801:Humans; D046911:Macromolecular Substances; D009682:Magnetic Resonance Spectroscopy; D008358:Mannose / Q000737:chemistry*; D013058:Mass Spectrometry; D010446:Peptide Fragments / Q000737:chemistry; D019699:Thrombospondins / Q000737:chemistry; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000737:chemistry
C101500:C(2)-mannosyltryptophan; D015938:Complement Membrane Attack Complex; D006020:Glycopeptides; D006023:Glycoproteins; D046911:Macromolecular Substances; D010446:Peptide Fragments; D019699:Thrombospondins; D014364:Tryptophan; D008358:Mannose